Minimally Invasive Monitoring Methods

ABSTRACT

The present invention provides methods for minimally invasive, long term monitoring of a physiological signal (e.g., neural signals) from a patient. In preferred embodiments, neural signals are sampled from the patient with an externally powered, leadless implanted device and are transmitted to an external device for further processing.

CROSS-REFERENCED TO RELATED APPLICATIONS

The present application claims benefit of U.S. Provisional PatentApplication Ser. No. 60/805,710, filed Jun. 23, 2006, to Harris et al.,entitled “Implantable Ambulatory Brain Monitoring System,” the completedisclosure of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to methods for sampling one ormore physiological signals from a patient. More specifically, thepresent invention relates to long term, ambulatory monitoring of one ormore neurological signals from a patient using a minimally invasivemethods.

Epilepsy is a disorder of the brain characterized by chronic, recurringseizures. Seizures are a result of uncontrolled discharges of electricalactivity in the brain. A seizure typically manifests itself as sudden,involuntary, disruptive, and often destructive sensory, motor, andcognitive phenomena. Seizures are frequently associated with physicalharm to the body (e.g., tongue biting, limb breakage, and burns), acomplete loss of consciousness, and incontinence. A typical seizure, forexample, might begin as spontaneous shaking of an arm or leg andprogress over seconds or minutes to rhythmic movement of the entirebody, loss of consciousness, and voiding of urine or stool.

A single seizure most often does not cause significant morbidity ormortality, but severe or recurring seizures (epilepsy) results in majormedical, social, and economic consequences. Epilepsy is most oftendiagnosed in children and young adults, making the long-term medical andsocietal burden severe for this population of patients. People withuncontrolled epilepsy are often significantly limited in their abilityto work in many industries and usually cannot legally drive anautomobile. An uncommon, but potentially lethal form of seizure iscalled status epilepticus, in which a seizure continues for more than 30minutes. This continuous seizure activity may lead to permanent braindamage, and can be lethal if untreated.

While the exact cause of epilepsy is often uncertain, epilepsy canresult from head trauma (such as from a car accident or a fall),infection (such as meningitis), or from neoplastic, vascular ordevelopmental abnormalities of the brain. Most epilepsy, especially mostforms that are resistant to treatment (i.e., refractory), are idiopathicor of unknown causes, and is generally presumed to be an inheritedgenetic disorder.

While there is no known cure for epilepsy, the primary treatment forthese epileptic patients are a program of one or more anti-epilepticdrugs or “AEDs.” Chronic usage of anticonvulsant and antiepilepticmedications can control seizures in most people. An estimated 70% ofpatients will respond favorably to their first AED monotherapy and nofurther medications will be required. However, for the remaining 30% ofthe patients, their first AED will fail to fully control their seizuresand they will be prescribed a second AED—often in addition to thefirst—even if the first AED does not stop or change a pattern orfrequency of the patient's seizures. For those that fail the second AED,a third AED will be tried, and so on. Patients who fail to gain controlof their seizures through the use of AEDs are commonly referred to as“medically refractory.”

For those patients with infrequent seizures, the problem is furthercompounded by the fact that they must remain on the drug for many monthsbefore they can discern whether there is any benefit. As a result,physicians are left to prescribe AEDs to these patients without clearand timely data on the efficacy of the medication. Because these drugsare powerful neural suppressants and are associated with undesirableside-effects and sedation, it is important to minimize the use anddosage of these drugs if the patient is not experiencing benefit.

A major challenge for physicians treating epileptic patients is gaininga clear view of the effect of a medication or incremental medications.Presently, the standard metric for determining efficacy of themedication is for the patient or for the patient's caregiver to keep adiary of seizure activity. However, it is well recognized that suchself-reporting is often of poor quality because patients often do notrealize when they have had a seizure, or fail to accurately recordseizures. In addition, patients often have “sub-clinical” seizures wherethe brain experiences a seizure, but the seizure does not manifestitself clinically, and the patient has no way of making note of suchseizures.

Demographic studies have estimated the prevalence of epilepsy atapproximately 1% of the population, or roughly 2.9 million individualsin the United States alone. In order to assess possible causes for theseizures and to guide treatment for these epileptic patients,epileptologists (both neurologists and neurosurgeons) typically admitthe patient to an epilepsy monitoring unit (“EMU”), where the patientwill undergo continuous video-EEG monitoring in an attempt to captureictal brain activity (“seizure activity”) and interictal brain activity.

During their stay in the EMU, the patients may be purposefully stressedin an attempt to induce seizure activity. For example, the patients areoften sleep deprived, and if the patients are on medication, themedications may be decreased or stopped. However, for patients who haveinfrequent seizures, even in such a stressed state, many of suchpatients do not have a seizure during their stay in the EMU, and suchcostly and time consuming in-hospital monitoring provides little or noinsight into the patient's condition.

While in-patient video-EEG monitoring is currently the standard of care,improvements are still needed. For example, one drawback that has notbeen addressed by video-EEG monitoring is the fact that the sleepdeprivation and/or a decrease or complete stoppage of the AEDs may causecluster seizures and/or induce status epilepticus—which may not bereflective of the patient's typical seizures or seizure frequency. Thus,the EEG data that is collected in the EMU may not accurately reflect thepatient's condition—which can complicate attempts to diagnose andproperly treat the patient.

Consequently, what are needed are methods and systems that are capableof long-term, out-patient monitoring of epileptic patients. It wouldfurther be desirable if the long-term monitoring could be processed intoappropriate metrics that can quantify the clinical benefit of themedication or other therapies. It would also be desirable to have systemthat could record seizure activity, to enable the meaningful study ofpatients with infrequent seizures.

SUMMARY OF THE INVENTION

The present invention provides methods and systems for monitoring one ormore physiological signals from the patient. In preferred embodiments,the present invention provides minimally-invasive systems that providefor the long-term, ambulatory monitoring of patient's brain activity.The systems of the present invention will typically include one or moreimplantable devices that are capable of sampling and transmitting asignal that is indicative of the patient's brain activity to a datacollection device that is external to the patient's body.

Instead of requiring the patient to stay in an EMU, where the patient'sare in an unnatural stressed situation, the systems and methods of thepresent invention allow for out of hospital monitoring and will allowthe patient to go about their lives substantially unimpeded. Theambulatory systems of the present invention provide for substantiallycontinuous sampling of brain wave electrical signals (e.g.,electroencephalography or “EEG” and electrocorticogram “ECoG”, which arehereinafter referred to collectively as “EEG”). The ambulatory systemsof the present invention are more likely to record the occurrence of aseizure—particularly for patients who have infrequent seizures.

A patient could wear their external data collection device at all timesof the day (except while showering, etc.). At the physicians' office,the data from the external data collection device could be uploaded intoa physician's computer, which could then automatically analyze thestored EEG data and calculate certain metrics that would provide insightinto the patient's condition. For example, such metrics may allow theepileptologist to determine if the patient is epileptic, determine thetype of epilepsy and seizures, localize one or more seizure focuses,assess seizure frequency, monitor for sub-clinical seizures, determinethe efficacy of treatment, determine the effect of adjustments of thedosage of the AED, determine the effects of adjustments of the type ofAED, adjust parameters of electrical stimulation, or the like.

The methods of the present invention typically make use of one or morelow power implantable devices for sampling the patient's EEG signal. Theimplantable devices are in communication with a device that is externalto the patient's body. The external device is typically configured totransmit power into the implantable device and to store the EEG signalthat is sampled by the implantable device. The implantable device andthe external device will be in communication with each other through awireless communication link. While any number of different wirelesscommunication links may be used, in preferred embodiments the systems ofthe present invention uses a high-frequency communication link. Such acommunication link enables transmission of power into the implantabledevice and facilitates data transfer to and from the implantable device.

In one aspect, the present invention provides a method of recordingneural signals from a patient. The method comprises receiving a wirelesssignal that interrogates and optionally powers an electronic componentof an implanted device that is positioned between the patient's scalpand an outer surface of the skull. The neural signals of the patient aresampled substantially continuously with electrodes coupled to theelectronic components of the implanted leadless device. A wirelesssignal is transmitted that is encoded with data that is indicative ofthe sampled neural signal from the implanted device to an externaldevice. The wireless signal that is encoded with data that is indicativeof the sampled neural signal is derived from the wireless signalreceived from the external device. The wireless signal can be any typeof wireless signal—radiofrequency signal, magnetic signal, opticalsignal, infrared signal, or the like.

In preferred embodiments, the implanted devices are leadless. Typically,implantation is carried out by accessing a space between at least onelayer of the scalp and skull with an introducer and injecting (orotherwise inserting) the leadless device into the space through a lumenof the introducer. Because of the high prevalence of temporal lobeepilepsy, in many embodiments, the leadless devices are positioned overthe patient's temporal lobe. Of course, the leadless devices may beimplanted in any desired area over the skull.

The sampling of the neural signals is preferably carried outsubstantially continuously, so as to provide a substantially continuousrecord of the patient's brain activity. The neural signals may besampled at any sampling rate, but is typically between about 200 Hz andabout 1000 Hz.

The neural signals are typically processed prior to transmitting thewireless signal from the patient's body. Processing may include anyconventional or proprietary method, but typically includes performing atleast one of amplifying, filtering, analog-to-digital converting,compressing, encrypting, and the like. In some embodiments, theimplanted devices may include some or all of a neural signal algorithm.The algorithm may comprise feature extractors and classifiers. As such,the processing may comprises extracting features (e.g., electricalbiomarkers) from the neural signals that are indicative of the patient'sbrain state. Such extracted figures may be encoded in the wirelesssignal that is transmitted to the external device. In one configuration,the extracted features are indicative of the patient's propensity for aneurological event, such as a seizure, tremor, migraine headache,episode of depression, or the like.

In another aspect, the present invention provides a method of performingbrain activity monitoring with a device that is external to a patient.The method comprises generating a wireless signal that is configured toprovide power to an implanted device and initiate sampling of a neuralsignal (e.g., EEG, temperature, concentration of chemicals in the brain,or the like) with the implanted device. A wireless data signal isreceived from the implanted device that is encoded with a sampled neuralsignal and the received data signal is processed in the device that isexternal to the patient. The processed data signal is thereafter storedin a memory.

In preferred embodiments, the implanted device is leadless and isimplantable in the patient in a minimally invasive fashion, e.g.,between the skull and at least one layer of the patient's scalp.

The wireless signal generated and transmitted to the leadless implanteddevice is typically a radiofrequency signal, but could also be anoptical signal, infrared signal, ultrasonic signal, magnetic signal orthe like. The wireless signal transmitted to the implanted device andreceived back from the implanted device typically has a sampling ratebetween about 200 Hz and about 1000 Hz. In addition to being encodedwith the sampled neural signal, the wireless signal received from theimplanted device may include an extracted feature that is indicative orpredictive of the patient's brain state. The brain state is typicallyindicative of the patient's propensity for a neurological event.

Processing the received signal in the external device may include anynumber of processing steps. Processing may include amplification,filtering, converting, decrypting, uncompressing, etc. For embodimentsthat are more than just a data collection device, the external devicemay comprise a portion or all of a neural signal algorithm. In suchembodiments, processing comprises running the data signal through thealgorithms to extract one or more features from the neural signals andclassifying the extracted feature(s) to estimate the patient's brainstate. The estimated brain state may be indicative or predictive of thepatient's propensity for a neurological event, such as a seizure,tremor, migraine headache, episode of depression, or the like.

The external device will typically include a user interface. The userinterface may be used to provide system status indication (such as anoutput regarding battery strength of the external device and a warningsignal when the implanted devices is out of communication range of theexternal device) and brain state indications (that indicate thepatient's different propensities for a neurological event)

In some embodiments, when it is estimated that the patient has anelevated propensity for a seizure, the external device may be configuredto generate a control signal that facilitates delivery of a therapy tothe patient. The therapy may be electrical stimulation that is deliveredby the implanted devices, or the therapy may be delivered by additionalimplanted devices—such as a deep brain stimulator, spinal cordstimulator, vagus nerve stimulator, cortical stimulator, implanted drugpumps, or the like.

In a further aspect, the present invention provides a method ofmonitoring and recording EEG signals from a patient. The methodcomprises minimally invasively implanting a leadless device between thepatient's scalp and skull. A radiofrequency signal is generated in anexternal device and the radiofrequency signal is received with anantenna of the implanted leadless device. The radiofrequency signal isused to power up and interrogate components of the implanted device. AnEEG signal is sampled with electrodes on the implanted leadless deviceand a return radiofrequency signal is transmitted from the implantedleadless device to the external device. The return radiofrequency signalis encoded with the EEG signal. The return radiofrequency signal encodedwith the EEG signal is received in the external device and is processedtherein. Thereafter, the processed return radiofrequency signal isstored in a memory of the external device.

The external device typically comprises a user interface that providesoutput communications to the patient implanted with the leadlessdevices. The user interface may be used to generate an output to thepatient that indicates their estimated brain state (e.g., propensity fora seizure). Additionally, the user interface may be used to indicatewhen the external device is not receiving the return radiofrequencysignal from the leadless implanted device. Such a signal may indicate tothe patient that the external device is out of communication range orthat there is a problem with one of the components of the system.

In some embodiments, the return radiofrequency signal is encrypted orotherwise protected so as to safeguard the patient's privacy.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1A illustrates a simplified system embodied by the presentinvention which comprises one or more implantable devices incommunication with an external device.

FIG. 1B illustrates simplified methods of operating the system of thepresent invention.

FIG. 2A illustrates a bottom view of one embodiment of an activeimplantable device that is encompassed by the present invention.

FIG. 2B illustrates a cross-sectional view of the active implantabledevice of FIG. 2A along lines B-B.

FIG. 2C is a linear implantable device that comprises a plurality ofelectrode contacts in which at least one electrode contact comprises theactive implantable device of FIG. 2A.

FIG. 2D is a cross sectional view of the implantable device of FIG. 2Calong lines D-D.

FIG. 2E is a 4×4 electrode array that comprises a plurality of electrodecontacts in which at least one electrode contact comprises the activeimplantable contact of FIG. 2A.

FIG. 3A is a cross-sectional view of another embodiment of animplantable device that is encompassed by the present invention.

FIG. 3B is a cross-sectional view of another embodiment of theimplantable device in which a conductive can forms a housing around theelectronic components and acts as an electrode.

FIG. 3C illustrates a simplified plan view of an embodiment thatcomprises four electrodes disposed on the implanted device.

FIG. 4 illustrates one embodiment of the electronic components that maybe disposed within the implantable device.

FIG. 5 is a block diagram illustrating one embodiment of electroniccomponents that may be in the external device.

FIG. 6 illustrates a simplified trocar or needle-like device that may beused to implant the implantable device beneath the patient's skin.

FIG. 7 illustrates a method of inserting an implantable device in thepatient and wirelessly sampling EEG signals from a patient.

FIG. 8 illustrates a method of lateralizing a seizure focus.

FIG. 9 illustrates a method of measuring seizure activity data forclinical and/or sub-clinical seizures.

FIG. 10 illustrates a method of evaluating efficacy of a therapy.

FIG. 11 illustrates a method of titrating an efficacious therapy.

FIG. 12 illustrates a simplified method of performing a clinical trial.

FIG. 13 illustrates a more detailed method of performing a clinicaltrial.

FIG. 14 is a kit that is encompassed by the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Certain specific details are set forth in the following description andfigures to provide an understanding of various embodiments of theinvention. Certain well-known details, associated electronics anddevices are not set forth in the following disclosure to avoidunnecessarily obscuring the various embodiments of the invention.Further, those of ordinary skill in the relevant art will understandthat they can practice other embodiments of the invention without one ormore of the details described below. Finally, while various processesare described with reference to steps and sequences in the followingdisclosure, the description is for providing a clear implementation ofparticular embodiments of the invention, and the steps and sequences ofsteps should not be taken as required to practice this invention.

The term “condition” is used herein to generally refer to the patient'sunderlying disease or disorder—such as epilepsy, depression, Parkinson'sdisease, headache disorder, etc. The term “state” is used herein togenerally refer to calculation results or indices that are reflective acategorical approximation of a point (or group of points) along a singleor multi-variable state space continuum of the patient's condition. Theestimation of the patient's state does not necessarily constitute acomplete or comprehensive accounting of the patient's total situation.As used in the context of the present invention, state typically refersto the patient's state within their neurological condition. For example,for a patient suffering from an epilepsy condition, at any point in timethe patient may be in a different states along the continuum, such as anictal state (a state in which a neurological event, such as a seizure,is occurring), a pre-ictal state (which is a neurological state thatimmediately precedes the ictal state), a pro-ictal state (a state inwhich the patient has an increased risk of transitioning to the ictalstate), an inter-ictal state (a state in between ictal states), acontra-ictal state (a protected state in which the patient has a lowrisk of transitioning to the ictal state within a calculated orpredetermined time period), or the like. A pro-ictal state maytransition to either an ictal or inter-ictal state. A pro-ictal statethat transitions to an ictal state may also be referred to herein as a“pre-ictal state.”

The estimation and characterization of “state” may be based on one ormore patient dependent parameters from the a portion of the patient'sbody, such as electrical signals from the brain, including but notlimited to electroencephalogram signals and electrocorticogram signals“ECoG” or intracranial EEG (referred to herein collectively as EEG”),brain temperature, blood flow in the brain, concentration of AEDs in thebrain or blood, changes thereof, etc.). While parameters that areextracted from brain-based signals are preferred, the present inventionmay also extract parameters from other portions of the body, such as theheart rate, respiratory rate, blood pressure, chemical concentrations,etc.

An “event” is used herein to refer to a specific event in the patient'scondition. Examples of such events include transition from one state toanother state, e.g., an electrographic onset of seizure, end of seizure,or the like. For conditions other than epilepsy, the event could be anonset of a migraine headache, onset of a depressive episode, a tremor,or the like.

The occurrence of a seizure may be referred to as a number of differentthings. For example, when a seizure occurs, the patient is considered tohave exited a “pre-ictal state” or “pro-ictal state” and hastransitioned into the “ictal state”. However, the electrographic onsetof the seizure (one event) and/or the clinical onset of the seizure(another event) have also occurred during the transition of states.

A patient's “propensity” for a seizure is a measure of the likelihood oftransitioning into the ictal state. The patient's propensity for seizuremay be estimated by determining which “state” the patient is currentlyin. As noted above, the patient is deemed to have an increasedpropensity for transitioning into the ictal state (e.g., have a seizure)when the patient is determined to be in a pro-ictal state. Likewise, thepatient may be deemed to have a low propensity for transitioning intothe ictal state when it is determined that the patient is in acontra-ictal state.

The methods, devices and systems of the present invention are useful forlong-term, ambulatory sampling and analysis of one or more physiologicalsignals, such as a patient's brain activity. In one preferredembodiment, the system of the present invention may be used to monitorand store one or more substantially continuously sampled EEG signalsfrom the patient, while providing a minimal inconvenience to thepatient. Attempts at developing ambulatory monitoring systems in thepast have relied on an array of electrodes being placed on the patient'shead and scalp with adhesive. Unfortunately, such systems are poorlytolerated by patients and are impractical for the duration of timeneeded for the accurate evaluation of the patient's EEG and evaluationof the efficacy of the treatment the patients are undergoing. Unlikeconventional ambulatory EEG systems, the ambulatory monitoring systemsof the present invention typically include one or more devices that areimplanted in a minimally invasive fashion in the patient and will belargely unnoticed by a patient as they go about their day-to-dayactivities. The implantable devices may be in wireless communicationwith an external device that may be carried by the patient or kept inclose proximity to the patient. Consequently, the ambulatory monitoringsystems of the present invention are conducive to longer, more effectivemonitoring of the patient (e.g., one week or longer, one month orlonger, two months or longer, three months or longer, six months orlonger, one year or longer, etc.).

The methods, devices and systems of the present invention may also finduse in an emergency room or neurological intensive care units (ICU). Forexample, the systems may be used to monitor patients who have complex,potentially life-threatening neurological illnesses or brain injuries.Neuro ICUs may monitor patients who have suffered (or thought to havesuffered) a stroke (e.g., cerebral infarction, transient ischemicattacks, intracerebral hemorrhage, aneurismal subarachnoid hemorrhage,arteriovenous malformations, dural sinus thrombosis, etc.), head trauma,spinal cord injury, tumors (e.g., spinal cord metastases, paraneoplasticsyndromes), infections (e.g., encephalitis, meningitis, brain abscess),neuromuscular weakness (e.g., Guillain-barre syndrome, myastheniagravis), eclampsia, neuropleptic malignant syndrome, CNS vasculitis,migraine headaches, or the like.

The neuro-ICUs require the ability to monitor the patient's neurologicalcondition for a long period of time to identify issues and diagnose thepatient before permanent neurological damage occurs. Because the systemsof the present invention are able to provide real-time monitoring of apatient's EEG and many embodiments have the ability to detect or predictneurological events, such systems will be beneficial to patients and thestaff of the ICU to allow the neurologist and support staff to detectand/or prevent complications that may arise from the patient'sneurological condition, before the patient's condition deteriorates.

For example, a patient who is suffering from head trauma may beoutfitted with a system of the present invention and because theimplantable portions are MRI safe, the patient's may still undergo MRIsessions. Furthermore, the systems of the present invention may also beused to continuously monitor a patient's response to a drug therapywhile the patient is in the neuro-ICU and when the patient leaves theneuro-ICU.

For epilepsy patients in particular, the monitoring systems of thepresent invention may be used in conjunction with, or as an alternativeto, the in-patient video-EEG monitoring that occurs in the EMU. If usedas an alternative to in-patient video-EEG monitoring, in someembodiments it may be desirable to provide one or more video recordersin the patient's home to provide time-synced video recording of thepatient as they live with their ambulatory monitoring system. In someembodiments, it may be desirable to provide a patient-mounted videosystem so as to allow video-monitoring of the patient outside of theirhome. Such a video system may or may not be in communication with theambulatory monitoring system of the present invention; but both thevideo and the monitored EEG signals should be time-synced and analyzedtogether by the physician to assess the patient's condition and/orefficacy of any therapy that the patient may be undergoing.

The systems and methods of the present invention may incorporate EEGanalysis software to estimate and monitor the patient's brain statesubstantially in real-time. The EEG analysis software may include asafety algorithm, a seizure prediction algorithm and/or a seizuredetection algorithm that uses one or more extracted features from theEEG signals (and/or other physiological signals) to estimate thepatient's brain state (e.g., predict or detect the onset of a seizure).Additionally, some systems of the present invention may be used tofacilitate delivery of a therapy to the patient to prevent the onset ofa predicted seizure and/or abort or mitigate a seizure after it hasstarted. Facilitation of the delivery of the therapy may be carried outby outputting a warning or instructions to the patient or automaticallydelivering a therapy to the patient (e.g., pharmacological, electricalstimulation, etc.). The therapy may be delivered to the patient usingthe implanted devices that are used to collect the ambulatory signals,or it may be delivered to the patient through a different implanteddevice. A description of some systems that may be used to delivery atherapy to the patient are described in commonly owned U.S. Pat. Nos.6,366,813 and 6,819,956, U.S. Patent Application Publication Nos.2005/0021103 (published Jan. 27, 2005), 2005/0119703 (published Jun. 2,2005), 2005/0021104 (published Jan. 27, 2005), 2005/0240242 (publishedOct. 27, 2005), 2005/0222626 (published Oct. 6, 2005), and U.S. patentapplication Ser. No. 11/282,317 (filed Nov. 17, 2005), Ser. Nos.11/321,897, 11/321,898, and 11/322,150 (all filed Dec. 28, 2005), thecomplete disclosures of which are incorporated herein by reference.

For patients suspected or known to have epilepsy, the systems of thepresent invention may be used to provide data and other metrics to thepatients and physicians that heretofore have not been accuratelymeasurable. For example, the data may be analyzed to (1) determinewhether or not the patient has epilepsy, (2) determine the type ofepilepsy, (3) determine the types of seizures, (4) localize orlateralize one or more seizure foci, (5) assess baseline seizurestatistics and/or change from the baseline seizure statistics (e.g.,seizure count, frequency, duration, seizure pattern, etc.) (6) monitorfor sub-clinical seizures, assess a baseline frequency of occurrence,and/or change from the baseline occurrence, (7) measure the efficacy ofAED treatments, (8) assess the effect of adjustments of the dosage ofthe AED, (9) determine the effects of adjustments of the type of AED,(10) determine the effect of, and the adjustment to parameters of,electrical stimulation (e.g., vagus nerve stimulation (VNS), deep brainstimulation (DBS), cortical stimulation, etc.), (11) determine“triggers” for the patient's seizures, (12) assess outcomes fromsurgical procedures, (13) provide immediate biofeedback to the patient,(14) screen patients for determining if they are an appropriatecandidate for a seizure advisory system or other neurological monitoringor therapy system, or the like.

The systems of the present invention typically include one or moreimplantable devices that are in wireless communication with an externaldata collection device, typically with a high frequency communicationlink. The implantable devices of the present invention are typicallyimplanted in a minimally invasive fashion beneath at least one layer ofthe scalp, above the patient's skull/calvarium, and over one or moretarget area of the patient's brain. As will be described in more detailbelow, the implantable devices are typically injected underneath theskin/scalp using an introducer, trocar or syringe-like device usinglocal anesthesia. It is contemplated that such a procedure could becompleted in 20 to 30 minutes by a physician or neurologist in anout-patient procedure.

The implantable devices are typically used to continuously sample thephysiological signals for a desired time period so as to be able tomonitor fluctuations of the physiological signal over substantially theentire time period. In alternative embodiments, however, the implantabledevices may be used to periodically sample the patient's physiologicalsignals or selectively/aperiodically monitor the patient's physiologicalsignals.

The implantable devices may be permanently or temporarily implanted inthe patient. If permanently implanted, the devices may be used for aslong as the monitoring is desired, and once the monitoring is completed,because the implanted devices are biocompatible they may remainpermanently implanted in the patient without any long term detrimentaleffects for the patient. However, if it is desired to remove theimplanted devices, the devices may be explanted from the patient underlocal anesthesia. For ease of removal, it may be desirable to tether orotherwise attach a plurality of the implantable devices together (e.g.,with a suture or leash) so that a minimal number of incisions are neededto explant the implantable devices.

Exact positioning of the implanted devices will usually depend on thedesired type of monitoring. For patients who are being monitored forepilepsy diagnosis, the suspected type of epilepsy may affect thepositioning of the implantable devices. For example, if the patient isthought to have temporal lobe epilepsy, a majority of the implantabledevices will likely be located over the patient's temporal lobe.Additionally, if the focus of the seizure is known, it may be desirableto place a plurality of implantable devices directly over the focus.However, if the focus has not been localized, a plurality of implantabledevices may be spaced over and around the target area of the patient'sbrain (and one or more implantable devices contralateral to the targetarea) in an attempt to locate or lateralize the seizure focus.

The number of implantable devices that are implanted in the patient willdepend on the number of channels that the physician wants toconcurrently monitor in the patient. Typically however, the physicianwill implant 32 or less, and preferably between about 2 and about 16implantable devices, and most preferably between about 4 and about 8implantable devices. Of course, in some instances, it may be desirableto implant more or less, and the present invention is not limited to theaforementioned number of implanted devices.

While the remaining discussion focuses on methods of using the systemsand devices of the present invention for ambulatory monitoring of EEGsignals of patients and patient populations for the diagnosis ofepilepsy and/or evaluation of the efficacy and dosing of the patient'sAEDs, it should be appreciated that the present invention is not limitedto sampling EEG signals for epilepsy or for monitoring the efficacy ofAEDs. For example, the implanted devices may be implanted under the skinof the patient's face, within the muscle of the patient's face, withinthe skull, above the jaw (e.g., sphenoidal implant that is placed underthe skin just above the jaw to monitor the brain activity in thetemporal lobes), or any other desired place on the patient's body.Furthermore, in addition to or as an alternative to monitoring EEGsignals from the patient, it may be desired to monitor otherphysiological signals from a patient. For example, the system of thepresent invention may be used to monitor one or more of a bloodpressure, blood oxygenation, temperature of the brain or other portionof the patient, blood flow measurements in the brain or other parts ofthe body, ECG/EKG, heart rate signals and/or change in heart ratesignals, respiratory rate signals and/or change in respiratory ratesignals, chemical concentrations of medications, pH in the blood orother portions of the body, other vital signs, other physiological orbiochemical parameters of the patient's body, or the like.

Furthermore, the systems of the present invention may be useful formonitoring and assisting in the analysis of treatments for a variety ofother neurological conditions, psychiatric conditions, episodic andnon-episodic neurological phenomenon, or other non-neurological andnon-psychiatric maladies. For example, the present invention may beuseful for patients suffering from sleep apnea and other sleepdisorders, migraine headaches, depression, Alzheimer's, Parkinson'sDisease, eating disorders, dementia, attention deficit disorder, stroke,cardiac disease, diabetes, cancer, or the like. Likewise, the presentinvention may also be used to assess the symptoms, efficacy ofpharmacological and electrical therapy on such disorders.

Referring now to the Figures, FIG. 1A illustrates a simplified system 10embodied by the present invention. System 10 includes one or moreimplantable devices 12 that are configured to sample electrical activityfrom the patient's brain (e.g., EEG signals). The implantable devicesmay be active (with internal power source), passive (no internal powersource), or semi-passive (internal power source to power components, butnot to transmit data signal). The implantable devices 12 may beimplanted anywhere in the patient, but typically one or more of thedevices 12 may be implanted adjacent a previously identified epilepticfocus or a portion of the brain where the focus is believed to belocated. Alternatively, the devices 12 themselves may be used to helpdetermine the location of the epileptic focus.

The physician may implant any desired number of devices in the patient.As noted above, in addition to monitoring brain signals, one or moreadditional implanted devices 12 may be implanted to measure otherphysiological signals from the patient.

While it may be possible to implant the implantable devices 12 under theskull and in or on the brain, it is preferred to implant the implantabledevices 12 in a minimally invasive fashion under at least one layer ofthe patient's scalp and above the skull. Implantable devices 12 may beimplanted between any of the layers of the scalp (sometimes referred toherein as “sub-galeal”). For example, the implantable devices may bepositioned between the skin and the connective tissue, between theconnective tissue and the epicranial aponeurosis/galea aponeurotica,between the epicranial aponeurosis/galea aponeurotica and the looseaerolar tissue, between the loose aerolar tissue and the pericranium,and/or between the pericranium and the calvarium. In someconfigurations, it may be useful to implant different implantabledevices 12 between different layers of the scalp.

Implantable devices 12 will typically be configured to substantiallycontinuously sample the brain activity of the groups of neurons in theimmediate vicinity of the implanted device. In some embodiments, ifplaced below the skull and in contact with the cortical surface of thebrain, the electrodes may be sized to be able to sample activity of asingle neuron in the immediate vicinity of the electrode (e.g., amicroelectrode). Typically, the implantable device 12 will beinterrogated and powered by a signal from the external device tofacilitate the substantially continuous sampling of the brain activitysignals. Sampling of the brain activity is typically carried out at arate above about 200 Hz, and preferably between about 200 Hz and about1000 Hz, and most preferably at about 400 Hz, but it could be higher orlower, depending on the specific condition being monitored, the patient,and other factors. Each sample of the patient's brain activity willtypically contain between about 8 bits per sample and about 32 bits persample, and preferably between about 12 bits per sample and about 16bits per sample. Thus, if each return communication transmission to theexternal device includes one EEG sample per transmission, and the samplerate is 400 Hz and there are 16 bits/sample, the data transfer rate fromthe implantable devices 12 to the external device 14 is at least about6.4 Kbits/second. If there are 32 implantable devices, the total datatransfer rate for the system 10 would be about 205 Kbits/second. Inalternative embodiments, it may be desirable to have the implantabledevices sample the brain activity of the patient in a non-continuousbasis. In such embodiments, the implantable devices 12 may be configuredto sample the brain activity signals periodically (e.g., once every 10seconds) or aperiodically.

Implantable device 12 may comprise a separate memory module for storingthe recorded brain activity signals, a unique identification code forthe device, algorithms, other programming, or the like.

A patient instrumented with the implanted devices 12 will typicallycarry a data collection device 14 that is external to the patient'sbody. The external device 14 would receive and store the signal from theimplanted device 12 with the encoded EEG data (or other physiologicalsignals). The external device is typically of a size so as to beportable and carried by the patient in a pocket or bag that ismaintained in close proximity to the patient. In alternativeembodiments, the device may be configured to be used in a hospitalsetting and placed alongside a patient's bed. Communication between thedata collection device 14 and the implantable device 12 typically takesplace through wireless communication. The wireless communication linkbetween implantable device 12 and external device 14 may provide acommunication link for transmitting data and/or power. External device14 may include a control module 16 that communicates with the implanteddevice through an antenna 18. In the illustrated embodiment, antenna 18is in the form of a necklace that is in communication range with theimplantable devices 12. It should be appreciated however, that theconfiguration of antenna 18 and control module 16 may be in a variety ofother conventional or proprietary forms. For example, in anotherembodiment control module 16 may be attached around an arm or belt ofthe patient, integrated into a hat, integrated into a chair or pillow,and/or the antenna may be integrated into control module 16.

In order to facilitate the transmission of power and data, the antennaof the external device and the implantable devices must be incommunication range of each other. The frequency used for the wirelesscommunication link has a direct bearing on the communication range.Typically, the communication range is between at least one foot,preferably between about one foot and about twenty feet, and morepreferably between about six feet and sixteen feet. As can beappreciated, however, the present invention is not limited to suchcommunication ranges, and larger or smaller communication ranges may beused. For example, if an inductive communication link is used, thecommunication range will be smaller than the aforementioned range.

In some situations, it may be desirable, to have a wire running from thepatient-worn data collection device 14 to an interface (not shown) thatcould directly link up to the implanted devices 12 that are positionedbelow the patient's skin. For example, the interface may take the formof a magnetically attached transducer, as with cochlear implants. Thiscould enable power to be continuously delivered to the implanted devices12 and provide for higher rates of data transmission.

In some configurations, system 10 may include one or more intermediatetransponder (not shown) that facilitates data transmission and powertransmission between implantable device 12 and external device 14. Theintermediate transponder may be implanted in the patient or it may beexternal to the patient. If implanted, the intermediate transponder willtypically be implanted between the implantable device 12 and theexpected position of the external device 14 (e.g., in the neck, chest,or head). If external, the transponder may be attached to the patient'sskin, positioned on the patient's clothing or other body-worn assembly(e.g., eyeglasses, cellular phone, belt, hat, etc.) or in a device thatis positioned adjacent the patient (e.g., a pillow, chair headrest,etc.). The intermediate transponder may be configured to only transmitpower, only transmit data, or it may be configured to transmit both dataand power. By having such intermediate transponders, the external device14 may be placed outside of its normal communication range from theimplanted devices 12 (e.g., on a patient's belt or in a patient's bag),and still be able to substantially continuously receive data from theimplantable device 12 and/or transmit power to the implantable device12.

Transmission of data and power between implantable device 12 andexternal device 14 is typically carried out through a radiofrequencylink, but may also be carried out through magnetic induction,electromagnetic link, Bluetooth® link, Zigbee link, sonic link, opticallink, other types of wireless links, or combinations thereof.

One preferred method 11 of wirelessly transmitting data and power iscarried out with a radiofrequency link, similar to the link used withradiofrequency identification (RFID) tags. As illustrated in FIGS. 1Aand 1B, in such embodiments, one or more radio frequency signals areemitted from the external device 14 through antenna 18 (step 13). If theexternal device 14 is in communication range of the implantable devices,at step 15 the radiofrequency (RF) energy signal illuminates thepassive, implantable devices 12.

At step 17 the same RF signal interrogates the energized implantabledevice 12 to allow the implantable device to sample the desiredphysiological signal from the patient (such as an EEG signal). At step19, the implantable device samples the instantaneous EEG signal (orother physiological signal) from the patient.

At step 21, the implantable device 12 then communicates a return RFsignal to the external device 14 that is encoded with data that isindicative of the sampled EEG signal. Typically, the return RF signal isa based on the RF signal generated by the external device and includesdetectable modifications which indicate the sampled EEG signal. Forexample, the return signal is typically a backscattering of the RFsignal from the external device with the detectable modifications thatindicate the sampled EEG signal. Advantageously, such backscatteringdoes not require generation of a separate radiating signal and would notrequire an internal power source. The return RF signals may also includethe identification code of the implanted device so as to identify whichdevice the data is coming from. At step 23, the return RF signal emittedby the internal device 12 is received by the antenna 18, and the RFsignal is decoded to extract the sampled EEG signal. The sampled EEGsignal may thereafter be stored in a memory of the external device 14.For embodiments in which the method is used to collect data, such datawill be stored until accessed by the patient. Typically, such data willbe analyzed on a separate device (e.g., physician's computerworkstation).

In alternative embodiments, however, in which the external device maycomprise software to analyze the data in substantially real-time, thereceived RF signal with the sampled EEG may be analyzed by the EEGanalysis algorithms to estimate the patient's brain state which istypically indicative of the patient's propensity for a neurologicalevent (step 25). The neurological event may be a seizure, migraineheadache, episode of depression, tremor, or the like. The estimation ofthe patient's brain state may cause generation of an output (step 27).The output may be in the form of a control signal to activate atherapeutic device (e.g., implanted in the patient, such as a vagusnerve stimulator, deep brain or cortical stimulator, implanted drugpump, etc.). In other embodiments, the output may be used to activate auser interface on the external device to produce an output communicationto the patient. For example, the external device may be used to providea substantially continuous output or periodic output communication tothe patient that indicates their brain state and/or propensity for theneurological event. Such a communication could allow the patient tomanually initiate therapy (e.g., wave wand over implanted vagus nervestimulator, cortical, or deep brain stimulator, take a fast acting AED,etc.) or to make themselves safe.

In preferred embodiments, the return RF signal is transmitted (e.g.,backscattered) immediately after sampling of the EEG signal to allow forsubstantially real-time transfer (and analysis) of the patient's EEGsignals. In alternate embodiments, however, the return RF signal may bebuffered in an internal memory and the communication transmission to theexternal device 14 may be delayed by any desired time period and mayinclude the buffered EEG signal and/or a real-time sampled EEG signal.The return RF signal may use the same frequency as the illumination RFsignal or it may be a different frequency as the illumination RF signal.

Unlike conventional digital implantable devices that send large packetsof stored data with each return RF communication transmission, someembodiment of the methods and devices of the present inventionsubstantially continuously sample physiological signals from the patientand communicate in real-time small amounts of data during each return RFsignal communication. Because only small amounts of data (one or a smallnumber of sampled EEG signals from each implantable device 12) aretransmitted during each communication, a lower amount of power isconsumed and the illumination of the implanted device from the incominghigh-frequency RF signal will be sufficient to power the implantabledevice 12 for a time that is sufficient to allow for sampling of thepatient's EEG signal. Consequently, in most embodiments no internalpower source, such as a battery, is needed in the implantable device12—which further reduces the package size of the implantable device 12.

The implantable devices 12 and the external devices 14 of the presentinvention typically use an electromagnetic field/high frequencycommunication link to both illuminate the implantable device and enablethe high data transfer rates of the present invention. Conventionaldevices typically have an internally powered implantable device and usea slower communication link (e.g., that is designed for long link accessdelays) and transmit data out on a non-continuous basis. In contrast,some embodiments of the present invention uses a fast accesscommunication link that transmits a smaller bursts of data (e.g., singleor small number of EEG sample at a time) on a substantially continuousbasis.

The frequencies used to illuminate and transfer data between theimplantable devices 12 and external device are typically between 13.56MHz and 10 GHz, preferably between 402 MHz and 2.4 GHz, more preferablybetween 900 MHz and 2.4 GHz. While it is possible to use frequenciesabove 2.4 GHz, Applicants have found that it is preferred to use afrequency below 2.4 GHz in order to limit attenuation effects caused bytissue. As can be appreciated, while the aforementioned frequencies arethe preferred frequencies, the present invention is not limited to suchfrequencies and other frequencies that are higher and lower may also beused. For example, it may be desirable us use the MICS (Medical ImplantCommunication Service band) that is between 402-405 MHz to facilitatethe communication link. In Europe, it may be desirable to use ETSI RFIDallocation 869.4-869.65 MHz.

While not illustrated in FIG. 1B, the system 10 of the present inventionmay also make use of conventional or proprietary forward errorcorrection (“FEC”) methods to control errors and ensure the integrity ofthe data transmitted from the implantable device 12 to the externaldevice 14. Such forward error correction methods may include suchconventional implementations such as cyclic redundancy check (“CRC”),checksums, or the like.

If desired, the data signals that are wirelessly transmitted fromimplantable device 12 may be encrypted prior to transmission to thecontrol module 16. Alternatively, the data signals may be transmitted tothe control module 16 as unencrypted data, and at some point prior tothe storage of the data signals in the control module 16 or prior totransfer of the data signals to the physician's office, the EEG data maybe encrypted so as to help ensure the privacy of the patient data.

FIGS. 3A and 3B illustrate two embodiments of the externally poweredleadless, implantable device 12 that may be used with the system 10 ofthe present invention. The implantable devices 12 of the presentinvention are preferably passive or semi-passive and are “slaves” to the“master” external device 14. The implantable devices will typicallyremain dormant until they are interrogated and possibly energized by anappropriate RF signal from the external device 14. As will be describedbelow, the implantable device 14 may have minimal electronic componentsand computing power, so as to enable a small package size for theimplantable device.

Advantageously, the embodiment illustrated in FIGS. 3A and 3B areminimally invasive and may be implanted with an introducer, trocar orsyringe-like device under local anesthesia by a physician or potentiallyeven a physician's assistant. Typically, the implanted device of FIG. 3Amay have a longitudinal dimension 20 of less than about 3 cm, andpreferably between about 1 cm and about 10 cm, and a lateral dimension22 of less than about 2 mm, and preferably between about 0.5 mm andabout 10 mm. As can be appreciated, such dimensions are merelyillustrative, and other embodiments of implanted device may have largeror smaller dimensions.

FIG. 3A illustrates an embodiment that comprises a first electrode 24and a second electrode 26 that are disposed on opposing ends of housing28. The first and second electrodes 24, 26 may be composed of platinum,platinum-iridium alloy, stainless steel, or any other conventionalmaterial. The electrodes may include a coating or surface treatment suchas platinum-iridium or platinum-black in order to reduce electricalimpedance. The first and second electrodes 24, 26 will typically have asmooth or rounded shape in order to reduce tissue erosion and may have asurface area of about 3 mm², but other embodiments may be smaller orlarger. Since electrodes 24, 26 are typically adapted to only sensephysiological signals and are not used to deliver stimulation, thesurface area of the electrodes may be smaller than conventionalimplantable devices. The smaller electrodes have the advantage ofreducing the overall device size which can be beneficial for improvingpatient comfort and reducing the risk of tissue erosion.

Housing 28 is typically in the form of a radially symmetrical,substantially cylindrical body that hermetically seals electroniccomponents 30 disposed within a cavity 32. Housing 28 may be composed ofa biocompatible material, such as glass, ceramic, liquid crystalpolymer, or other materials that are inert and biocompatible to thehuman body and able to hermetically seal electronic components. Housing28 may have embedded within or disposed thereon one or more x-rayvisible markers 33 that allow for x-ray localization of the implantabledevice. Alternatively, one or more x-ray visible markers may be disposedwithin the cavity 32. Cavity 32 may be filled with an inert gas orliquid, such as an inert helium nitrogen mixture which may also be usedto facilitate package leakage testing. Alternatively, it may bedesirable to fill the cavity 32 with a liquid encapsulant (not shown)that hardens around the electronic components. The liquid encapsulantmay comprise silicone, urethane, or other similar materials.

While housing 28 is illustrated as a substantially cylindrical body withthe electrodes 24, 26 on opposing ends, housing may take any desiredshape and the electrodes may be positioned at any position/orientationon the housing 28. For example, housing 28 may taper in one direction,be substantially spherical, substantially oval, substantially flat, orthe like. Additionally or alternatively, the body may have one or moresubstantially planar surfaces so as to enhance the conformity to thepatient's skull and to prevent rotation of the implantable device 12.While not shown, housing 28 may optionally include a conductiveelectromagnetic interference shield (EMI) that is configured to shieldthe electronic components 30 in housing 28. The EMI shield may bedisposed on an inner surface of the housing, outer surface of thehousing, or impregnated within the housing.

If desired, housing 28 may optionally comprise an anchoring assembly(not shown) that improves the anchoring of the implantable device 12 tothe skull or the layers within the scalp. Such anchoring may be carriedout with adhesive, spikes, barbs, protuberances, suture holes, sutures,screws or the like.

In the illustrated embodiment, first electrode 24 is disposed on a firstend of housing 28 and is in electrical communication with the electroniccomponents 30 through a hermetic feedthrough 34. Feedthrough 34 may bethe same material as the first electrode 24 or it may be composed of amaterial that has a similar coefficient of thermal expansion as thehousing 28 and/or the first electrode 24. Feedthrough 34 may make directcontact with a pad (not shown) on a printed circuit board 36, or anyother type of conventional connection may be used (e.g., solder ball,bond wire, wire lead, or the like) to make an electrical connection tothe printed circuit board 36.

Second electrode 26 may be spaced from a second, opposing end of thehousing 28 via an elongated coil member 38. In the illustratedembodiment, the second electrode 26 typically comprises a protuberance39 that is disposed within and attached to a distal end of the coilmember 38. Coil member 38 acts as an electrical connection betweensecond electrode and the electronic components 30 disposed withinhousing 28.

Coil member 38 will typically be composed of stainless steel, a highstrength alloy such as MP35N, or a combination of materials such as aMP35N outer layer with silver core.

The illustrated embodiment shows that coil member 38 has a largestlateral dimension (e.g., diameter) that is less than the largest lateraldimension (e.g., diameter) of housing 28, but in other embodiments, thecoil may have the same lateral dimension or larger lateral dimensionfrom housing 28.

Coil member 38 may also be used as an antenna to facilitate the wirelesstransmission of power and data between the implantable device 12 and theexternal device 14 (or other device). In preferred embodiments, coilmember 38 may be used to receive and transmit radiofrequency signals. Inalternative embodiments, however, coil member 38 may be inductivelycoupled to an external coil to receive energy from a modulating,alternating magnetic field. Unlike other conventional implantabledevices, the RF antenna is disposed outside of the housing 28 andextends from one end of housing 28. It should be appreciated however,that the present invention is not limited to a substantially cylindricalantenna extending from an end of the housing 28 and various otherconfigurations are possible. For example, it may be desirable to windthe antenna around or within the housing 28. Furthermore, it may bedesirable to use a substantially flat antenna (similar to RFID tags) tofacilitate the transmission of power and data. To facilitateimplantation, such antennas may be rolled into a cylindrical shape andbiased to take the flat shape upon release from the introducer.

While not shown, it may also be desirable to provide a second antennabetween the first electrode 24 and the housing 28. The second antennamay be used for power and downlink using a first frequency, e.g., 13.56MHz, while the first antenna may be used for uplink using a secondfrequency, e.g., 902-928 MHz. In such embodiments, however, theimplantable devices would need to have an internal timebase (e.g.,oscillator and a frequency synthesizer). For the embodiments that useonly a single frequency for the downlink and uplink, an internaltimebase or frequency synthesizer is not needed—and the timebaseestablished by the master (e.g., external device 14) can be used.

Coil member 38 may be in electrical communication with the electroniccomponents 30 with a hermetic feedthrough 42 that extends through a via44 in housing 28. Feedthrough 42 is typically composed of a materialthat has a coefficient of thermal expansion that is substantiallysimilar to the material of housing 40. Because the coil member 38 isoutside of the housing 28 the length of the implantable device 12 willbe increased, but the flexible coil will be better exposed to the RFsignals and will be allowed to conform to the shape of the patient'sskull.

Coil member 38 is typically disposed outside of the housing 28 anddisposed within an elongate, substantially flexible housing 40. Comparedto the more rigid housing 28, the flexible housing 40 is better able toconform to the shape of an outer surface of the patient's skull, morecomfortable for the patient and reduces the chance of tissue erosion.Flexible housing 40 may comprise silicone, polyurethane, or the like Inthe illustrated embodiment, flexible housing 40 extends along the entirelength of coil member 38, but in other embodiments, flexible housing 40may extend less than or longer than the longitudinal length of coilmember 38. Flexible housing 40 will typically have a substantiallycylindrical shape, but if desired a proximal end 46 of the cylindricalhousing may be enlarged or otherwise shaped to substantially conform toa shape of the housing 28. The shaped proximal end 46 may be adhered orotherwise attached to the end of the housing 40 to improve the hermeticseal of the housing and may reduce any potential sharp edge ortransition between the housings 28, 40. While FIG. 3A only illustrates asingle layered flexible housing, if desired, the flexible housing 40 maycomprise a plurality of layers, and the different layers may comprisedifferent types of materials, have embedded x-ray markers, or the like.

A longitudinal length of flexible housing 40 and the longitudinal lengthof the rigid housing 28 may vary depending on the specific embodiment,but a ratio of the longitudinal length of the flexible housing 40: thelongitudinal length of the more rigid housing 28 is typically betweenabout 0.5:1 and about 3:1, and preferably between about 1:1 and about2:1. By having the longitudinal length of the flexible housing longerthan the longitudinal length of the rigid housing, advantageously theimplantable device will be more comfortable and better able to conformto the outer surface of the patient's skull. In alternative embodiments,it may also be desirable to have a longitudinal length of the rigidhousing 28 be longer than the longitudinal length of the flexiblehousing 40, or in any other desired configuration.

Because the implantable devices 12 of the present invention consume aminimal amount of energy and use a high frequency RF coupling to powerthe device and communicate the EEG signals to the external device,unlike other conventional devices, some of the implantable devices 12 ofthe present invention will not need a ferrite core to store energy, andthe electronic components 30 of the present invention will typicallyinclude aluminum or other MRI-safe material. Consequently, the patient'simplanted with the implantable device 12 may safely undergo MRI imaging.

FIG. 3B illustrates another embodiment of implantable device 12 that isencompassed by the present invention. The embodiment of FIG. 3B sharesmany of the same components as the embodiment of FIG. 3A, and suchcomponents are noted with the same reference numbers as FIG. 3A. Thereare, however, a few notable exceptions. Specifically, instead of havinga hermetically sealed housing, the embodiment of FIG. 3B provides aconductive body 48 that acts as both the housing for the electroniccomponents 30 and as the second electrode. Conductive body 48 may becomposed of a metallized polymer, one or more metal or metal alloys, orother conductive material. Because body 48 is conductive, it may act asan electromagnetic interference (EMI) shield to the electroniccomponents disposed within the cavity 32. Electrical connections to theprinted circuit board 36 may be carried out with one or more conductivespring conductors 50 or other conventional lead connectors.

Feedthrough 42 that is connected to the coil member 38 extends from theend of coil member 38 and makes an electrical connection with a lead onthe printed circuit board 36. The feedthrough 42 works in conjunctionwith one or more dielectric seals or spacers 52 to hermetically seal thecavity 32. Similar to above, the cavity 32 may be filled with an inertgas or an encapsulant. The proximal end 46 of flexible body 40 may becoupled to the seals 52 and/or coupled to the conductive body 48.

As shown in the embodiment of FIG. 3B, the surface area of conductivebody 48 (e.g., the first electrode) may be larger than the surface areaof the second electrode 26. In other embodiments, however, the surfacearea of the second electrode 26 may have the substantially same surfacearea and/or shape as the conductive body 48.

In most embodiments, the implantable devices shown in FIGS. 3A and 3Bfunction completely independent of the other implantable devices 12 andthere is no physical connection or communication between the variousdevices. If desired, however, the implantable devices 12 may bephysically coupled to each other with a connecting wire or tether and/orin communication with each other. If the plurality of implanted devices12 are in communication with one another, it may be desired to use acommunication frequency between the implanted devices 12 that isdifferent from the frequency to communicate between the implanteddevices and the external device 14. Of course, the communicationfrequency between the implanted devices 12 may also be the samefrequency as the communication frequency with the external device 14.

While FIGS. 3A and 3B illustrate a first and second electrode 24, 26,the implantable devices 12 of the present invention are not limited toonly two electrodes. Any number of electrodes may be coupled to theimplantable device in any orientation. For example, the electrodes donot have to extend from ends of the housing, but may be positionedanywhere along a portion of the housings 28, 40. Furthermore, aplurality of electrodes and their leads may be disposed along the lengthof the flexible housing 40 and/or rigid housing 28 so as to provide morethan two electrodes per implantable device. For example, FIG. 3Cillustrates a simplified embodiment in which there are two additionalelectrode 24′, 26′ positioned on the rigid housing 28 and flexiblehousing 40, respectively. The spacing between the various contacts 24,24′, 26, 26′ may vary or be the same distance between each other. Thespacing between electrodes will likely depend on the overall length ofthe implantable device, but will typically be between about 2 mm andabout 20 mm and preferably be between about 5 mm and about 10 mm. Inaddition to the embodiment shown in FIG. 3C, it may be desirable to havethe additional electrodes only on the flexible housing 40 or only on therigid housing 28. While only four electrodes are shown on the implanteddevice, it should be appreciated that any desirable number of electrodes(e.g., anywhere between two electrodes and about sixteen electrodes) maycoupled to the implanted device.

While FIGS. 3A-3B illustrate some currently preferred embodiments of theimplantable device 12, the present invention further encompasses othertypes of minimally invasive implantable devices 12 that can monitor thebrain activity and other physiological signals from the patient. Forexample, a plurality of electrodes might reside on a single lead thatcould be tunneled under the scalp from a single point of entry. Examplesof such embodiments are shown in FIGS. 2A-2E.

Such implantable devices 12 include an active electrode contact 400 thatis in communication with one or more passive electrode contacts 401. Theactive electrode contact 400 may be used to facilitate monitoring of thephysiological signals using the array of active and passive electrodecontacts. The arrays of electrode contacts may be arranged in a linearorientation (FIG. 2C) or in a grid pattern (FIG. 2E), or any otherdesired pattern (e.g., circular, star pattern, customized asymmetricpattern, etc.) For example, if the implantable device comprises twoelectrode contacts (e.g., one active contact and one passive contact),such an embodiment would have a similar configuration as the embodimentof FIG. 3A. Similarly, if the implantable device were to have foursubstantially linearly positioned electrode contacts (e.g., one activecontact and three passive contacts), such an embodiment would besubstantially similar to the configuration shown in FIG. 3C.

FIG. 2A illustrates a bottom view of an active electrode contact 400that may be part of the implantable device 12 of the present invention.The active electrode contact comprises a base 402 that is coupled to acontact portion 404. The base 402 and contact portion may be composed ofany number of different types of materials, such as platinum,platinum-iridium alloy, stainless steel, or any other conventionalmaterial. In preferred embodiments, both the base 402 and contactportion 404 are formed to their desired shape. The base 402 may comprisea plurality of hermetic feedthroughs 413 that is implemented usingconventional glass metal seal technology (e.g., pins 408, glass seal414, and vias 406). The hermetic feedthroughs 413 may be used to connectto an antenna (not shown) for communication with the external device 14or to make an electrical connection with an adjacent passive electrodecontact 401 in the implanted device 12. In the illustrated embodiment,base 402 comprises four hermetic feedthroughs 413. But as can beappreciated the base 402 may comprise any desired number of feedthroughs413 (e.g., anywhere between two and sixty four feedthroughs).

FIG. 2B illustrates a cross-sectional view of the active electrodecontact 400 along lines B-B in FIG. 2A. As shown in FIG. 2B, the contactportion 404 is shaped to as to align the base 402 along a bottom surfacedefined by flanges 409. Base 402 may be coupled to the contact portion404 with a laser weld, glass metal seal, or other conventional connector410 along an outer perimeter of the base 402 to hermetically sealcomponents of the active electrode contact within a cavity 412 definedby the base 402 and contact portion 404. If desired, the cavity 412 maybe backfilled with nitrogen and/or helium to facilitate package leaktesting.

A thin or thick filmed microcircuit or a printed circuit board (“PCB”)416 may be mounted onto an inner surface of the base 402. PCB 416 mayhave active components 418 (e.g., integrated circuits, ASIC, memory,etc.) and passive components 420 (e.g., resistors, capacitors, etc.)mounted thereto. Leads or bond wires 422 from the active and passivecomponents may be electrically attached to pads on the PCB (not shown)which make electrical connections to leads or bond wires 424 that areattached to the hermetic feedthroughs 413. While not shown in FIG. 2B,the active electrode contact 400 may comprise a rechargeable ornon-rechargeable power supply (e.g., batteries), and/or x-ray visiblemarkers (not shown).

As noted above, the active contacts may be used in conjunction with oneor more passive contacts to form an active implantable device 12 tofacilitate monitoring of the patient's physiological signals and tocommunicate with the external device 14. FIGS. 2C and 2D illustrate anembodiment of the implantable device 12 in which one active contact 400is housed in a body 426 along with a plurality of passive contacts 401to form a multiple contact implantable device 12. The contact portion ofthe active contact 400 is exposed through an opening in the body 426 toallow for sampling of the physiological signals (e.g., EEG) from thepatient. The body 426 may be substantially flexible or rigid and mayhave similar dimensions and/or shapes as the embodiments shown in FIGS.3A-3C. Body 426 may be composed of a biocompatible material such assilicone, polyurethane, or other materials that are inert andbiocompatible to the human body. Body 426 may also be composed of arigid material such as polycarbonate. The implantable device may beinjected into the patient using the introducer assembly shown in FIG. 6and methods shown in FIG. 7.

As shown in FIG. 2D wire leads 427 may extend from the passive contacts401 and be electrically and physically coupled to one of the hermeticfeedthroughs 413 of the active contact 400 to facilitate sampling of thephysiological signals using all four electrode contacts. For embodimentswhich use a wireless link (e.g., RF) to wirelessly transmit data to theexternal device 14 and optionally to power the device, one of thefeedthroughs may be coupled to an antenna 428 that is configured towirelessly communicate with the external device. It should beappreciated, that while not described herein, the embodiments of FIGS.2C-2E may have any of the components or variations as described above inrelation to FIGS. 3A-3B.

FIG. 2E illustrates an alternative embodiment of the implantable device12 in which the implantable device 12 is in the form of a 4×4 grid arrayof active and passive contacts. At least one of the electrode contactsmay be an active contact 400 so as to facilitate monitoring of thepatient's physiological signals with the array. In the illustratedembodiment, the contacts in the leftmost column (highlighted withcross-hatching) are active electrode contacts 400, and the contacts inremaining column are electrically connected to one of the activecontacts 400. Of course, any number of active contacts 400 and passivecontacts 401 may be in the grid array and the active contact(s) 400 maybe positioned anywhere desired. For example, if the active electrodecontact 400 has sixteen or more hermetic feedthroughs, only one of thecontacts in the array needs to be active and the remaining fifteencontacts could be passive contacts.

FIG. 4 illustrates one simplified embodiment of the electroniccomponents 30 (e.g., active components 418 and passive components 420 inFIG. 2B) that may be disposed in the implantable devices 12 as shown inFIGS. 2A-3C. It should be appreciated, however, that the electroniccomponents 30 of the implantable device 12 may include any combinationof conventional hardware, software and/or firmware to carry out thefunctionality described herein. For example, the electronic components30 may include many of the components that are used in passive RFintegrated circuits.

The first and second electrodes will be used to sample a physiologicalsignal from the patient—typically an EEG signal 53, and transmit thesampled signal to the electronic components 30. While it may be possibleto record and transmit the analog EEG signal to the external device, theanalog EEG signal will typically undergo processing before transmissionto the external device 14. The electronic components typically include aprinted circuit board that has, among others, an amplifier 54, one ormore filters 56 (e.g., bandpass, notch, lowpass, and/or highpass) and ananalog-to-digital converter 58. In some embodiments, the processed EEGsignals may be sent to a transmit/receive sub-system 60 for wirelesstransmission to the external device via an antenna (e.g., coil member38). Additional electronic components that might be useful inimplantable device 12 may be found in U.S. Pat. Nos. 5,193,539,5,193,540, 5,312,439, 5,324,316, 5,405,367 and 6,051,017.

In some alternative embodiments of the present invention, the electroniccomponents 30 may include a memory 64 (e.g., RAM, EEPROM, Flash, etc.)for permanently or temporarily storing or buffering the processed EEGsignal. For example, memory 64 may be used as a buffer to temporarilystore the processed EEG signal if there are problems with transmittingthe data to the external device. For example, if the external device'spower supply is low, the memory in the external device is removed, or ifthe external device is out of communication range with the implantabledevice, the EEG signals may be temporarily buffered in memory 64 and thebuffered EEG signals and the current sampled EEG signals may betransmitted to the external device when the problem has been corrected.If there are problems with the transmission of the data from theimplantable device, the external device may be configured to provide awarning or other output signal to the patient to inform them to correctthe problem. Upon correction of the problems, the implantable device mayautomatically continue the transfer the temporarily buffered data andthe real-time EEG data to the memory in the external device.

The electronic components 30 may optionally comprise dedicated circuitryand/or a microprocessor 62 (referred to herein collectively as“microprocessor”) for further processing of the EEG signals prior totransmission to the external device. The microprocessor 62 may executeEEG analysis software, such as a seizure prediction algorithm, a seizuredetection algorithm, safety algorithm, or portions of such algorithms,or portions thereof. For example, in some configurations, themicroprocessor may run one or more feature extractors that extractfeatures from the EEG signal that are relevant to the purpose ofmonitoring. Thus, if the system is being used for diagnosing ormonitoring epileptic patients, the extracted features (either alone orin combination with other features) may be indicative or predictive of aseizure. Once the feature(s) are extracted, the microprocessor 62 maysend the extracted feature(s) to the transmit/receive sub-system 60 forthe wireless transmission to the external device and/or store theextracted feature(s) in memory 64. Because the transmission of theextracted features is likely to include less data than the EEG signalitself, such a configuration will likely reduce the bandwidthrequirements for the communication link between the implantable deviceand the external device. Since the extracted features do not add a largeamount of data to the data signal, in some embodiments, it may also bedesirable to concurrently transmit both the extracted feature and theEEG signal. A detailed discussion of various embodiments of theinternal/external placement of such algorithms are described in commonlyowned U.S. patent application Ser. No. 11/322,150, filed Dec. 28, 2005to Bland et al., the complete disclosure of which is incorporated hereinby reference.

While most embodiments of the implantable device 12 are passive and doesnot need an internal power source or internal clock, in someembodiments, the electronic components 30 may include a rechargeable ornon-rechargeable power supply 66 and an internal clock (not shown). Therechargeable or non-rechargeable power supply may be a battery, acapacitor, or the like. The rechargeable power supply 66 may also be incommunication with the transmit/receive sub-system 60 so as to receivepower from outside the body by inductive coupling, radiofrequency (RF)coupling, etc. Power supply 66 will generally be used to provide powerto the other components of the implantable device. In such embodiments,the implanted device may generate and transmit its own signal with thesampled EEG signal for transmission back to the external device.Consequently, as used herein “transmit” includes both passivetransmission of a signal back to the external device (e.g.,backscattering of the RF signal) and internal generation of a separatesignal for transmission back to the external device.

FIG. 5 is a simplified illustration of some of the components that maybe included in external device 14. Antenna 18 and a transmit/receivesubsystem 70 will receive a data signal that is encoded with the EEGdata (or other physiological data) from the antenna 38 of theimplantable device 12 (FIG. 4). As used herein, “EEG data” may include araw EEG signal, a processed EEG signal, extracted features from the EEGsignal, an answer from an implanted EEG analysis software (e.g., safety,prediction and/or detection algorithm), or any combination thereof.

The EEG data may thereafter be stored in memory 72, such as a harddrive, RAM, permanent or removable Flash Memory, or the like and/orprocessed by a microprocessor 74 or other dedicated circuitry.Microprocessor 74 may be configured to request that the implantabledevice perform an impedance check between the first and secondelectrodes and/or other calibrations prior to EEG recording and/orduring predetermined times during the recording period to ensure theproper function of the system.

The EEG data may be transmitted from memory 72 to microprocessor 74where the data may optionally undergo additional processing. Forexample, if the EEG data is encrypted, it may be decrypted. Themicroprocessor 74 may also comprise one or more filters that filter outhigh-frequency artifacts (e.g., muscle movement artifacts, eye-blinkartifacts, chewing, etc.) so as to prevent contamination of the highfrequency components of the sampled EEG signals. In some embodiments,the microprocessor may process the EEG data to measure the patient'sbrain state, detect seizures, predict the onset of a future seizure,generate metrics/measurements of seizure activity, or the like. A morecomplete description of seizure detection algorithms, seizure predictionalgorithms, and related components that may be implemented in theexternal device 14 may be found in pending, commonly owned U.S. patentapplication Ser. Nos. 11/321,897 and 11/321,898, filed on Dec. 28, 2005,to Leyde et al. and DiLorenzo et al., and 60/897,551, filed on Jan. 25,2007, to Leyde et al., the complete disclosures of which areincorporated herein by reference.

It should be appreciated, however, that in some embodiments some or allof the computing power of the system of the present invention may beperformed in a computer system or workstation 76 that is separate fromthe system 10, and the external device 14 may simply be used as a datacollection device. In such embodiments, the personal computer 76 may belocated at the physician's office or at the patient's home and the EEGdata stored in memory 72 may be uploaded to the personal computer 76 viaa USB interface 78, removal of the memory (e.g., Flash Memory stick), orother conventional communication protocols, and minimal processing maybe performed in the external device 14. In such embodiments, thepersonal computer 76 may contain the filters, decryption algorithm, EEGanalysis software, such as a prediction algorithm and/or detectionalgorithm, report generation software, or the like. Some embodiments ofthe present invention may take advantage of a web-based datamonitoring/data transfer system, such as those described in U.S. Pat.Nos. 6,471,645 and 6,824,512, the complete disclosures of which areincorporated herein by reference.

External device 14 may also comprise an RF signal generator 75 that isconfigured to generate the RF field for interrogating and optionallypowering the implanted devices 12. RF generator 75 will be under controlof the microprocessor 74 and generate the appropriate RF field tofacilitate monitoring and transmission of the sampled EEG signals to theexternal device.

External device 14 will typically include a user interface 80 fordisplaying outputs to the patient and for receiving inputs from thepatient. The user interface typically comprise outputs such as auditorydevices (e.g., speakers) visual devices (e.g., LCD display, LEDs toindicate brain state or propensity to seizure), tactile devices (e.g.,vibratory mechanisms), or the like, and inputs, such as a plurality ofbuttons, a touch screen, and/or a scroll wheel.

The user interface may be adapted to allow the patient to indicate andrecord certain events. For example, the patient may indicate thatmedication has been taken, the dosage, the type of medication, mealintake, sleep, drowsiness, occurrence of an aura, occurrence of aseizure, or the like. Such inputs may be used in conjunction with therecorded EEG data to improve the analysis of the patient's condition anddetermine the efficacy of the medications taken by the patient.

The LCD display of the user interface 80 may be used to output a varietyof different communications to the patient including, status of thedevice (e.g., memory capacity remaining), battery state of one or morecomponents of system, whether or not the external device 14 is withincommunication range of the implantable devices 12, brain stateindicators (e.g., a warning (e.g., seizure warning), a prediction (e.g.,seizure prediction), unknown brain state, safety indication, arecommendation (e.g., “take drugs”), or the like). Of course, it may bedesirable to provide an audio output or vibratory output to the patientin addition to or as an alternative to the visual display on the LCD. Inother embodiments, the brain state indicators may be separate from theLCD display to as to provide a clear separation between the devicestatus outputs and the brain state indicators. In such embodiments, theexternal device may comprise different colored LEDs to indicatedifferent brain states. For example, a green LED may indicate a safebrain state, a yellow light may indicate an unknown brain state, and ared light may indicate either a seizure detection or seizure prediction.

External device may also include a medical grade power source 82 orother conventional power supply that is in communication with at leastone other component of external device 14. The power source 82 may berechargeable. If the power source 80 is rechargeable, the power sourcemay optionally have an interface for communication with a charger 84.While not shown in FIG. 5, external device 14 will typically comprise aclock circuit (e.g., oscillator and frequency synthesizer) to providethe time base for synchronizing external device 14 and the internaldevice(s) 12. In preferred embodiments, the internal device(s) 12 areslaves to the external device and the implantable devices 12 will nothave to have an individual oscillator and a frequency synthesizer, andthe implantable device(s) 12 will use the “master” clock as its timebase. Consequently, it may be possible to further reduce the size of theimplantable devices.

In use, one or more of the implantable devices are implanted in thepatient. The implanted device is interrogated and powered so that theEEG signals are sampled from the patient's brain. The EEG signals areprocessed by the implanted device and the processed EEG signals arewirelessly transmitted from the implanted device(s) to an externaldevice. The EEG signals are stored for future or substantially real-timeanalysis.

As noted above, in preferred embodiments, the implantable devices areimplanted in a minimally invasive fashion under the patient's scalp andabove an outer surface of the skull. FIG. 6 illustrates a simplifiedintroducer assembly 90 that may be used to introduce the implantabledevices into the patient. The introducer assembly 90 is typically in theform of a cannula and stylet or a syringe-like device that can accessthe target area and inject the implanted device under the skin of thepatient. As noted above, the implantable devices 12 are preferablyimplanted beneath at least one layer of the patient's scalp and abovethe patient's skull. Because of the small size of the implantabledevices 12, the devices may be injected into the patient under localanesthesia in an out-patient procedure by the physician or neurologist.Because the implantable devices are implanted entirely beneath the skininfection risk would be reduced and there would be minimal cosmeticimplications. Due to the small size of the implantable devices 12, itmay be desirable to have a plurality of implantable devices pre-loadedinto a sterile introducer assembly 90 or into a sterile cartridge (notshown) so as to minimize the risk of contamination of the implantabledevices 12 prior to implantation.

FIG. 7 schematically illustrates one example of a minimally invasivemethod 100 of implanting the implantable devices for ambulatorymonitoring of a patient's EEG signals. At step 102, an incision is madein the patient's scalp. At step 104, an introducer assembly is insertedinto the incision and a distal tip of the introducer assembly ispositioned at or near the target site. Of course, the introducerassembly itself may be used to create the incision. For example, if theintroducer assembly is in the form of a syringe, the syringe tip may bemade to create the incision and steps 102 and 104 may be consolidatedinto a single step. At step 106, the introducer assembly is actuated toinject the implantable device 12 to the target site. If desired, theintroducer may be repositioned to additional target sites underneath thepatient's skin and above the skull. If needed, additional incisions maybe created in the patient's skin to allow for injection of theimplantable device 12 at the additional target sites. After a desirednumber of implantable devices are placed in the patient, at step 108 theintroducer assembly is removed from the target site. At step 110, theimplantable devices are activated and used to perform long termmonitoring of the patient's EEG signals from each of the target sites.At step 112, the sampled EEG signals are then wirelessly transmitted toan external device. At step 114, the sampled EEG signals may then bestored in a memory in the external device or in another device (e.g.,personal computer). If desired, the EEG signals may then be processed inthe external device or in a personal computer of the physician.

While not shown in FIG. 7, it may also be desirable to anchor theimplantable devices to the patient to reduce the likelihood that theimplantable devices are dislodged from their desired position. Anchoringmay be performed with tissue adhesive, barbs or other protrusions,sutures, or the like.

Advantageously, the implantable devices are able to monitor EEG signalsfrom the patient without the use of burr holes in the skull orimplantation within the brain—which significantly reduces the risk ofinfection for the patient and makes the implantation process easier.While there is some attenuation of the EEG signals and movementartifacts in the signals, because the implantable devices are below theskin, it is believed that there will be much lower impedance than scalpelectrodes. Furthermore, having a compact implantable device 14 belowthe skin reduces common-mode interference signals which can cause adifferential signal to appear due to any imbalance in electrodeimpedance and the skin provides some protection from interference causedby stray electric charges (static).

While FIG. 7 illustrates one preferred method of implanting theimplantable devices in the patient and using the implantable devices tomonitor the patient's EEG, the present invention is not limited to sucha method, and a variety of other non-invasive and invasive implantationand monitoring methods may be used. For example, while minimallyinvasive monitoring is the preferred method, the systems and devices ofthe present invention are equally applicable to more invasivemonitoring. Thus, if it is desired to monitor and record intracranialEEG signals (e.g., ECoG), then it may be possible to implant one or moreof the implantable devices inside the patient's skull (e.g., in thebrain, above or below the dura mater, or a combination thereof) througha burr hole created in the patient's skull.

Once implanted in the patient, the monitoring systems 10 of the presentinvention may be used for a variety of different uses. For example, inone usage the systems of the present invention may be used to diagnosewhether or not the patient has epilepsy. Patients are often admitted tovideo-EEG monitoring sessions in an EMU to determine if the patient ishaving seizures, pseudo-seizures, or is suffering from vaso-vagalsyncope, and the like. Unfortunately, if the patient has infrequent“seizures,” it is unlikely that the short term stay in the EMU willrecord a patient's seizure and the patient's diagnose will still beunclear. Consequently, in order to improve the patient's diagnosis, inaddition to the in-hospital video-EEG monitoring or as an alternative tothe in-hospital video-EEG monitoring, the patient may undergo anambulatory, long term monitoring of the patient's EEG using the systemof the present invention for a desired time period. The time period maybe one day or more, a week or more, one month or more, two months ormore, three months or more, six months or more, one year or more, or anyother desired time period in between. The patient may be implanted withthe system 10 using the method described above, and after apredetermined time period, the patient may return to the physician'soffice where the EEG data will be uploaded to the physician's personalcomputer for analysis. A conventional or proprietary seizure detectionalgorithm may be applied to the EEG data to determine whether or not aseizure occurred in the monitoring time period. If it is determined thatone or more seizures occurred during the monitoring period, the seizuredetection algorithm may be used to provide an output to the physician(and/or generate a report for the patient) indicating the occurrence ofone or more seizures, and various seizure activity metrics, such asspike count over a period of time, seizure count over a period of time,average seizure duration over a period of time, the pattern of seizureoccurrence over time, and other seizure and seizure related metrics. Inaddition, the software may be used to display the actual EEG signalsfrom specific events or selected events for physician confirmation ofseizure activity. Such data may be used as a “baseline” for the patientwhen used in assessing efficacy of AEDs or other therapies that thepatient will undergo.

If the patient has been diagnosed with epilepsy (either using the systemof the present invention or through conventional diagnosis methods), thepresent invention may also be used to determine the epilepsyclassification and/or seizure type. To perform such methods, a desirednumber of implantable devices may be implanted in the patient for thelong term monitoring of the patient's pattern of electrical activity inthe different portions of the patient's brain. Such monitoring will beable to provide insight on whether or not the patient has partial/focalseizures or generalized seizures. In the event that the patient'sepilepsy classification is already known, the classification maydetermine the desired placement for the implantable devices in thepatient. For patients suspected or known to have temporal lobe epilepsy,the implantable devices will likely be focused over the temporal lobeand adjacent and/or over the regions of epileptiform activity. Likewise,for patient's suspected or known to have parietal lobe epilepsy, some orall of the implantable devices will be positioned over the parietal lobeand adjacent and/or over the regions of epileptiform activity.Furthermore, if the seizure focus or foci are known, at least some ofthe implantable devices may be positioned over the seizure focus or fociand some may be positioned contralateral to the known seizure focus orfoci.

If a seizure focus in the patient has not been lateralized, the presentinvention may be used to lateralize the seizure focus. FIG. 8illustrates one method 120 of lateralizing a seizure focus in a patient.At step 122, a set of implantable devices are implanted beneath at leastone layer of the patient's scalp and above the patient's skull (or belowthe skull, if desired). Preferably, the implantable devices willcomprise more than two electrodes to improve the ability to localize theseizure focus. For embodiments that only include two electrodes, a verylarge number of implantable devices may be required to actually localizethe seizure focus. In one embodiment, implantation may be carried outusing the method steps 102-108 illustrated in FIG. 7. At step 124, theset of implantable devices are used to sample the patient's EEG signals.At step 126, each of the EEG signals from the implantable devices areanalyzed over a period of time (e.g., with EEG analysis software, suchas a seizure detection algorithm) to monitor the patient's seizureactivity and once a seizure has occurred try to lateralize the seizurefocus. At step 128, if the seizure focus is lateralized, a subset of theimplantable devices that are lateralized to the seizure focus areidentified. At steps 130 and 132, the EEG signals from the subset ofimplantable may continue to be sampled, and such EEG signals maythereafter be stored and processed to analyze the patient's brainactivity. The implantable devices that are not lateralized to the focusmay be removed from the patient, disabled, or the EEG signals from suchimplantable devices may be ignored or not captured/stored. However, ifdesired, such EEG signals may continue to be stored and processed. Thelocation and/or lateralization of the seizure focus may thereafter beused by the physicians to determine whether or not the patient is acandidate for resective surgery or other procedures.

In another use, the present invention may be used to quantify seizureactivity statistics for the patient. The most common method ofquantifying a patient's seizure activity is through patient selfreporting using a seizure diary. Unfortunately, it has been estimatedthat up to 63% of all seizures are missed by patients. Patient's missingthe seizures are usually caused by the patients being amnesic to theseizures, unaware of the seizures, mentally incapacitated, the seizuresoccur during sleep, or the like. FIG. 9 illustrates a simplified method140 of measuring and reporting a patient's seizure activity statistics.At step 142, one or more implantable devices are implanted in a patient,typically in a minimally invasive fashion as shown in FIG. 7. At step144, the implantable devices are used to substantially continuouslysample EEG signals from the patient. At step 146, the sampled EEGsignals are wirelessly transmitted from the implantable device to anexternal device. At step 148, the sampled EEG signals are stored in amemory. At step 150, the stored EEG signals are analyzed with EEGanalysis software, typically using a seizure prediction and/or detectionalgorithm, to derive statistics for the clinical seizures and/or thesub-clinical seizures for the patient based on the long-term, ambulatoryEEG data. For example, the following statistics may be quantified usingthe present invention:

-   -   Seizure count over a time period—How many clinical and        sub-clinical seizures does the patient have in a specific time        period?

Seizure frequency—How frequent does the patient have seizures? What isthe seizure frequency without medication and with medication? Withoutelectrical stimulation and with electrical stimulation?

-   -   Seizure duration—How long do the seizures last? Without        medication and with medication? Without electrical stimulation        and with electrical stimulation?    -   Seizure timing—When did the patient have the seizure? Do the        seizures occur more frequently at certain times of the day?    -   Seizure patterns—Is there a pattern to the patient's seizures?        After certain activities are performed? What activities appear        to trigger seizures for this particular patient?

Finally, at step 152, report generation software may be used to generatea report based on the statistics for the seizure activity. The reportmay include some or all of the statistics described above, anepilepsy/no epilepsy diagnosis, identification of a seizure focus, andmay also include the EEG signal(s) associated with one or more of theseizures. The report may include text, graphs, charts, images, or acombination thereof so as to present the information to the physicianand/or patient in an actionable format. Advantageously, the systems maybe used to generate a baseline report for the patient, and the systemmay be continuously used to record data over a long period of time andprovide a quantification of the patient's change in their conditionand/or the efficacy of any therapy that the patient is undergoing(described in more detail below).

As noted above, the present invention enables the documentation and longterm monitoring of sub-clinical seizures in a patient. Because thepatient is unaware of the occurrence of sub-clinical seizures,heretofore the long term monitoring of sub-clinical seizures was notpossible. Documentation of the sub-clinical seizures may further provideinsight into the relationship between sub-clinical seizures and clinicalseizures, may provide important additional information relevant to theeffectiveness of patient therapy, and may further enhance thedevelopment of additional treatments for epilepsy.

FIG. 10 illustrates one exemplary method of how the seizure activitydata may be used to evaluate the efficacy or clinical benefit of acurrent or potential therapy and allow for the intelligent selection ofan appropriate therapy for an individual patient and/or stopping theusage of ineffective therapies. Currently, effectiveness of the AEDtherapy is based on self-reporting of the patient, in which the patientmakes entries in a diary regarding the occurrence of their seizure(s).If the entries in the patient diary indicate a reduction in seizurefrequency, the AED is deemed to be effective and the patient continueswith some form of the current regimen of AEDs. If the patient entries inthe patient diary do not indicate a change in seizure frequency, theAEDs are deemed to be ineffective, and typically another AED isprescribed—and most often in addition to the AED that was deemed to beineffective. Because AEDs are typically powerful neural suppressants andare associated with undesirable side-effects, the current methodology ofassessing the efficacy of the AEDs often keeps the patient onineffective AEDs and exposes the patient to unnecessary side-effects.

By way of example, a medically refractory patient coming to an epilepsycenter for the first time might first have the system of the presentinvention implanted and then asked to collect data for a prescribed timeperiod, e.g., 30 days. The initial 30 days could be used to establish abaseline measurement for future reference. The physician could thenprescribe an adjustment to the patient's medications and have thepatient collect data for another time period, e.g., an additional 30 dayperiod. Metrics from this analysis could then be compared to theprevious analysis to see if the adjustment to the medications resultedin an improvement. If the improvement was not satisfactory, the patientcan be taken off of the unsatisfactory medication, and a new medicationcould be tried. This process could continue until a satisfactory levelof seizure control was achieved. The present invention provides a metricthat allows physicians and patients to make informed decisions on theeffectiveness and non-effectiveness of the medications.

FIG. 10 schematically illustrates one example of such a method. At step162, one or more implantable devices are implanted in the patient,typically in a minimally-invasive fashion. At step 164, the one or moreimplantable devices are used to monitor the patient's EEG to obtain abaseline measurement for the patient. The baseline measurement istypically seizure activity statistics for a specific time period (e.g.,number of seizures, seizure duration, seizure pattern, seizurefrequency, etc.). It should be appreciated however, that the baselinemeasurement may include any number of types of metrics. For example, thebaseline metric may include univariate, bivariate, or multivariatefeatures that are extracted from the EEG, or the like. In one preferredembodiment, the baseline measurement is performed while the patient isnot taking any AEDs or using any other therapy. In other embodiments,however, the patient may be taking one or more AEDs and the baselinemeasurement will be used to evaluate adjustments to dosage or efficacyof other add-on therapies.

At step 166, the therapy that is to be evaluated is commenced. Thetherapy will typically be an AED and the patient will typically haveinstructions from the neurologist, epileptologist, or drug-manufacturerregarding the treatment regimen for the AED. The treatment regimen maybe constant (e.g., one pill a day) throughout the evaluation period, orthe treatment regimen may call for varying of some parameter of thetherapy (e.g., three pills a day for the first week, two pills a day forthe second week, one pill a day for the third week, etc.) during theevaluation period. During the evaluation period, the implantabledevice(s) will be used to substantially continuously sample thepatient's EEG and assess the effect that the AED has on the patient'sEEG. The sampled EEG may thereafter be processed to obtain a follow-upmeasurement for the patient (Step 168). If the baseline measurement wasseizure statistics for the baseline time period, then the follow-upmeasurement will be the corresponding seizure statistics for theevaluation period. At step 170, the baseline measurement is compared tothe follow-up measurement to evaluate the therapy. If the comparisonindicates that the therapy did not significantly change the patient'sbaseline, the therapy may be stopped, and other therapies may be tried.

Currently, the primary metric in evaluating the efficacy of an AED iswhether or not the AED reduces the patient's seizure count. In additionto seizure count, the systems of the present invention would be able totrack any reduction in seizure duration, modification in seizurepatterns, reduction in seizure frequency, or the like. While seizurecount is important, because the present invention is able to providemuch greater detail than just seizure count, efficacy of an AED may bemeasured using a combination of additional metrics, if desired. Forexample, if the patient was having a large number of sub-clinicalseizures (which the patient was not aware of) and the AED was effectivein reducing or stopping the sub-clinical seizures, the systems of thepresent invention would be able to provide metrics for such a situation.With conventional patient diary “metrics”, the patient and physicianwould not be aware of such a reduction, and such an AED would bedetermined to be non-efficacious for the patient. However, because thepresent invention is able to provide metrics for the sub-clinicalseizures, the efficacious medication could be continued, if desired.

At step 172, the epileptologist or neurologist may decide to change oneor more parameters of the therapy. For example, they may change adosage, frequency of dosage, form of the therapy or the like, andthereafter repeat the follow-up analysis for the therapy with thechanged parameter. After the “second” follow up measurement is complete,the second follow up data may be obtained and thereafter compared to the“first” follow up measurements and/or the baseline measurements. Whilenot shown in FIG. 10, the method may also comprise generating a reportthat details the patient's metrics, change in metrics, recommendations,etc.

In addition to evaluating an efficacy of a therapy for an individualpatient, the metrics that are provided by the present invention alsoenable an intelligent titration of a patient's medications. As shown inFIG. 11, if the patient is on a treatment regimen of an efficacioustherapy, the present invention may be used to reduce/titrate a dosage orfrequency of intake of the AED or AEDs, or other pharmacological agents.At step 182, one or more implantable devices are minimally invasivelyimplanted in the patient. Typically, the patient will already be on atreatment regimen of the efficacious therapy, but if not, theefficacious therapy is commenced with the prescribed parameters, e.g.,“standard” dosage (Step 184). At step 186, the patient's EEG (and/orother physiological signal) is monitored for a desired time period toobtain a first patient data measurement for the patient (e.g., thebaseline measurement). Similar to previous embodiments, the firstpatient data measurement may be any desired metrics, but will typicallybe clinical seizure frequency, clinical seizure duration, sub-clinicalseizure frequency, sub-clinical seizure duration, medication sideeffects. At step 188, after the baseline measurement has been taken, thefirst efficacious therapy is stopped and a therapy with at least onechanged parameter is started (referred to as “therapy with secondparameters” in FIG. 11). Typically, the changed parameter will be areduction in dosage, but it could be changing a frequency of the samedosage, a change in formulation or form of the same AED, or the like.

At step 190, the patient's EEG is monitored and processed to obtain asecond patient data measurement for the patient (e.g., follow-up datameasurement). If the neurologist or epileptologist is satisfied with theresults, the titration may end. But in many embodiments, the titrationprocess will require more than one modification of parameters of thetherapy. In such embodiments, the second therapy is stopped (step 192),and a therapy with N^(th) parameters (e.g., third, fourth, fifth . . . )is commenced (step 194). Monitoring and processing of the patient's EEGsignals are repeated (step 196), and the process is repeated a desirednumber of times (as illustrated by arrow 197). Once the desired numbersof modifications to the therapy have been made, the various patient datameasurements may be analyzed (e.g., compared to each other) to determinethe most desirous parameters for the therapy (step 198). As can beimagined, any number of different analyses or statistical methods may beperformed. In one embodiment, seizure activity statistics (e.g.,clinical seizure frequency, sub-clinical seizure frequency, seizure rateper time period, seizure duration, seizure patterns, etc.) may be usedto assess the efficacy and differences between the therapies.

With the instrumentation provided by the present invention, the processof selecting appropriate AEDs and the titration of dosages of such AEDscould occur much faster and with much greater insight than ever before.Further, the chance of a patient remaining on an incremental AED thatwas providing little incremental benefit would be minimized. Once apatient was under control, the patient could cease the use of thesystem, but the implantable device could remain in the patient. In thefuture, the patient might be asked to use the system again should theircondition change or if the efficacy of the AED wane due to toleranceeffects, etc.

While FIGS. 10 and 11 are primarily directed toward assessing theefficacy of a pharmacological agent (e.g., AED), such methods areequally applicable to assessing the efficacy and optimizingpatient-specific parameters of non-pharmacological therapies. Forexample, the present invention may also be used to evaluate and optimizeparameters for the electrical stimulation provided by the Vagus NerveStimulator (sold by Cyberonics Corporation), Responsive Neurostimulator(RNS) (manufactured by NeuroPace Corporation), Deep Brain Stimulators(manufactured by Medtronic), and other commercial and experimentalneural and spinal cord stimulators.

Furthermore, the systems of the present invention will also be able toprovide metrics for the effectiveness of changes to various electricalparameters (e.g., frequency, pulse amplitude, pulse width, pulses perburst, burst frequency, burst/no-burst, duty cycle, etc.) for theelectrical stimulation treatments. Such metrics will provide a reliableindication regarding the effectiveness of such parameter changes, andcould lead to optimization of stimulation for parameters for individualpatients or the patient population as a whole.

In addition to facilitating the selection of appropriate AEDs andtitration of dosages of the AEDs for an individual patient, the presentinvention may have beneficial use in the clinical trials for thedevelopment of experimental AEDs and other therapies for the epilepticpatient population (and other neurological conditions). One of thegreatest barriers to developing new AEDs (and other pharmacologicalagents) is the costs and difficulties associated with the clinicaltrials. Presently, the standard metric for such clinical trials ispatient seizure count. Because this metric is self-reported andpresently so unreliable, to power the study appropriately clinicaltrials for AEDs must involve very large patient populations, in whichthe patient's must have a high seizure count. At an estimated cost of$20,000 per patient for pharmacological trials, the cost of developing anew drug for epilepsy is exceedingly high and may deter drug companiesfrom developing AEDs.

The minimally invasive systems of the present invention may be used tofacilitate these clinical trials. Such systems could result insignificantly more reliable data, which would result in much smallersample patient populations, and could include a broader types ofpatients (e.g., patient's who don't have frequent seizures) forappropriately powering the study. Improved certainty in efficacy wouldalso reduce risk to the company, as it moved from safety studies toefficacy studies. Significantly reducing risk and improving theeconomics of these studies by reducing the required number of studysubjects could lead to an increase in the development of new therapiesfor this patient population, and other patient populations.

It should be appreciated however, that the present invention is notlimited to clinical trials for epilepsy therapies, and the presentinvention has equal applicability to other clinical trials (e.g., cancertherapy, cardiac therapy, therapy for other neurological disorders,therapy for psychiatric disorders, or the like.)

FIGS. 12-13 illustrate some methods of performing clinical trials thatare encompassed by the present invention. The present invention isapplicable to any type of clinical trial, including but not limited to arandomized clinical trial, e.g., an open clinical trial, asingle-blinded study, a double-blinded study, a triple-blinded study, orthe like.

FIG. 12 illustrates a simplified method 200 of performing a clinicaltrial according to the present invention. At step 201 participants areenrolled in the clinical trial. At step 202, selected participants inthe clinical trial are implanted with one or more leadless, implantabledevices (such as those described above) in order to sample one or morephysiological signal from the patient. Typically, the physiologicalsignal is an EEG signal. In preferred embodiments, the EEG signal issampled substantially continuously for the entire baseline period foreach of the participants in the clinical trial. In alternativeembodiments, it may be desirable to sample the EEG signals in anon-continuous basis.

At step 204, the sampled EEG signals are processed for a desired timeperiod to obtain a first patient data measurement, e.g., a baseline datameasurement, for each of the participants in the clinical trial. Afterthe participants have commenced the experimental therapy (typically byfollowing a prescribed treatment regimen by the investigator or drugcompany), the same implantable devices are used to sample the EEGsignals from the participant for an evaluation period, and the EEGsignals are processed to provide a second patient data measurement,e.g., follow-up measurement (Step 206, 208). At step 210, the baselinedata measurement and the follow-up data measurement may be comparedusing conventional statistical methods in order to evaluate theexperimental therapy on the patient population.

While not shown in FIG. 12, it may be desirable to have a “second”evaluation period (and a second follow-up measurement) in which at leastone parameter of the experimental therapy is changed and the changedexperimental therapy is administered to the patient. Similar to themethod of FIG. 11, such a method may provide guidance to finding theappropriate dosing, formulation, and/or form of delivery of theexperimental therapy.

The baseline period and the evaluation period are typically the sametime length. The time length may be any desired time, but is typicallyat least one week, and preferably between at least one month and atleast three months.

Evaluation of the experimental therapy may be to evaluate dosingrequirements, evaluate toxicity of the experimental therapy, evaluatelong-term adverse effects of the experimental therapy or to determineefficacy of the experimental therapy. In one preferred embodiment, thecomparison may simply determine whether there was a statisticallysignificant change in a seizure count between the baseline period andthe evaluation period. But as noted above, the baseline data measurementand follow-up data measurement may include any metric that is extractedfrom the EEG signals.

FIG. 13 illustrates a more detailed method of performing a clinicaltrial according to the present invention. At step 222 participants areenrolled in the clinical trial. At step 224, the participants in theclinical trial are implanted with one or more leadless, implantabledevices (such as those described above) in order to sample one or morephysiological signal from the patient. Typically, the physiologicalsignal is an EEG signal. In preferred embodiments, the EEG signal issampled substantially continuously for the entire baseline period foreach of the participants in the clinical trial.

At step 226, the sampled EEG signals are processed to obtain a firstpatient data measurement, e.g., a baseline data measurement, for each ofthe participants in the clinical trial. If the patient's do not have anyseizures during the baseline period, then the patient's will most likelybe excluded from the remainder of the clinical trial. The remainingparticipants in the clinical trial are then broken into an interventiongroup and a control group. The experimental therapy is commenced in theintervention group of the patient population (step 228), and a placebotherapy is commenced in the control group of the patient population(step 230).

The implantable devices are used to substantially continuously samplethe EEG signals of both the intervention group and the control groupduring an evaluation period. The EEG signals are processed to obtainfollow-up seizure activity data (or some other metric) for both groups(step 232, 234). Thereafter, the baseline data and the follow up datafor both the intervention group and the control group are analyzed,(e.g., compared with each other) to evaluate the efficacy of theexperimental therapy for the patient population (step 236). While notshown in FIG. 13, the method may further include changing one or moreparameters of the experimental therapy and comparing the “second” followup data to the baseline data and/or other follow up data.

While the preferred embodiments described above are directed towardevaluating experimental AEDs in the clinical trial, the presentinvention is equally applicable to clinical trials for otherexperimental pharmacological agents, biologics, devices, and othernon-pharmacological therapies. For example, the present invention mayalso be used to evaluate the Vagus Nerve Stimulator (sold by CyberonicsCorporation), Responsive Neurostimulator (RNS) (manufactured byNeuroPace Corporation), Deep Brain Stimulators manufactured byMedtronic, and other commercial and experimental neural and spinal cordstimulators. The minimally invasive systems of the present invention maybe implanted in patients who are equipped with any of the abovestimulators to provide metrics regarding the efficacy of the electricalstimulation treatments.

Furthermore, the systems of the present invention will also be able toprovide metrics for the effectiveness of changes to various electricalparameters (e.g., frequency, pulse amplitude, pulse width, pulses perburst, burst frequency, burst/no-burst, etc.) for the electricalstimulation treatments. Such metrics will provide a reliable indicationregarding the effectiveness of such parameter changes, and could lead tooptimization of stimulation for parameters for individual patients orthe patient population as a whole.

FIG. 14 illustrates a packaged system or kit 300 that is encompassed bythe present invention. The packaged system 300 may include a package 302that has one or more compartments for receiving an introducer assembly304 and one or more implantable devices 12. The introducer 304 istypically in the form of a syringe-like device or a cannula and stylet.The implantable device 12 may include any of the embodiments describedherein. One or more of the implantable devices 12 may be pre-loadedwithin the introducer 304. In other embodiments, the implantable devices12 may be loaded in its separate sterile packaging (shown in dottedlines) for easy loading into the introducer 304. The packaged system 300may include instructions for use (“IFU”) 306 that describe any of themethods described herein.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. For example, thepresent invention also encompasses other more invasive embodiments whichmay be used to monitor the patient's neurological system.

Alternative embodiments of the implantable device of the presentinvention may require a neurosurgeon to create a more invasive incisionin the patient's scalp. For example, it may be desirable to use a lowprofile device that is not substantially cylindrical, but instead issubstantially planar or concave so as to conform to the curvature of thepatient's skull. Such embodiments would likely not be able to beimplanted without general anesthesia and may require a surgeon toimplant the device.

On the other hand, in some embodiments it may be desirable to becompletely non-invasive. Such embodiments include “implantable” devices12 that are not actually implanted, but instead are “wearable” and maybe attached to the outer surface of the skin with adhesive or a bandageso as to maintain contact with the patient's skin. For example, it maybe possible to surface mount the device 12 behind the ears, in thescalp, on the forehead, along the jaw, or the like. Because theelectrodes are wireless and are such a small size, unlike conventionalelectrodes, the visual appearance of the electrodes will be minimal.

Furthermore, in some embodiments, it may be desirable to modify theimplantable device 12 to provide stimulation to the patient. In suchembodiments, the implantable device 12 will include a pulse generatorand associated hardware and software for delivering stimulation to thepatient through the first and second electrodes 24, 26 (or otherelectrodes coupled to the device. In such embodiments, the externaldevice 14 will include the hardware and software to generate the controlsignals for delivering the electrical stimulation to the patient.

While the above embodiments describe that power to the implanted devicesmay be derived wirelessly from an external device and/or from a batteryin the implanted device, it should be appreciated that the internaldevices may derive or otherwise “scavenge” power from other types ofconventional or proprietary assemblies. Such scavenging methods may beused in conjunction with the external power source and/or the internalpower source, or it may be used by itself to provide the necessary powerfor the implanted devices. For example, the implanted devices mayinclude circuitry and other assemblies (e.g., a microgenerator) thatderive and store power from patient-based energy sources such as kineticmovement/vibrations (e.g., gross body movements), movement of organs orother bodily fluids (e.g., heart, lungs, blood flow), and thermalsources in the body (e.g., temperature differences and variations acrosstissue). As can be imagined, such technology could reduce or eliminatethe need for recharging of an implanted battery, replacement of adepleted battery, and/or the creation of an external RF field—and wouldimprove the ease of use of the devices by the patients.

Some embodiments of the monitoring system may include an integralpatient diary functionality. The patient diary may be a module in theexternal device and inputs by the patient may be used to providesecondary inputs to provide background information for the sampled EEGsignals. For example, if a seizure is recorded, the seizure diary mayprovide insight regarding a trigger to the seizure, or the like. Thediary may automatically record the time and date of the entry by thepatient. Entries by the patient may be a voice recording, or throughactivation of user inputs on the external device. The diary may be usedto indicate the occurrence of an aura, occurrence of a seizure, theconsumption of a meal, missed meal, delayed meal, activities beingperformed, consumption of alcohol, the patient's sleep state (drowsy,going to sleep, waking up, etc.), mental state (e.g., depressed,excited, stressed), intake of their AEDs, medication changes, misseddosage of medication, menstrual cycle, illness, or the like. Thereafter,the patient inputs recorded in the diary may also be used by thephysician in assessing the patient's epilepsy state and/or determine theefficacy of the current treatment. Furthermore, the physician may beable to compare the number of seizures logged by the patient to thenumber of seizures detected by the seizure detection algorithm.

It is intended that the following claims define the scope of theinvention and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

1. A method of recording neural signals from a patient, the methodcomprising: receiving a wireless signal that interrogates an electroniccomponent of an implanted device that is positioned between thepatient's scalp and an outer surface of the skull; sampling the neuralsignal of the patient with electrodes coupled to the electroniccomponents of the implanted device; and substantially continuouslytransmitting a wireless signal that is encoded with data that isindicative of the sampled neural signal from the implanted device to anexternal device, wherein the wireless signal that is encoded with datathat is indicative of the sampled neural signal is derived from thewireless signal received.
 2. The method of claim 1 wherein the implanteddevice is leadless.
 3. The method of claim 2 wherein minimallyinvasively implanting the leadless device between the patient's scalpand skull comprises accessing a space between the patient's scalp andskull with an introducer and injecting the leadless device into thespace through a lumen of the introducer.
 4. The method of claim 3wherein the implanted leadless device is implanted over a temporal lobeof the patient's brain.
 5. The method of claim 1 wherein sampling theneural signal of the patient is performed substantially continuously fora time period of at least one day.
 6. The method of claim 1 wherein theneural signal comprises an extracranial EEG signal.
 7. The method ofclaim 1 further comprising extracting desired features from the neuralsignal prior to transmitting, wherein the wireless signal transmitted tothe external device is also encoded with the extracted feature.
 8. Themethod of claim 1 wherein the received wireless signal provides power tothe electronic components of the implanted device.
 9. The method ofclaim 1 wherein the received wireless signal and transmitted wire signalare radiofrequency signals.
 10. A method of performing brain activitymonitoring with a device that is external to a patient, the methodcomprising: generating a wireless signal that is configured to providepower to an implanted device and initiate sampling of a neural signalwith the implanted device; receiving a substantially continuous wirelessdata signal from the implanted device that is encoded with a sampledneural signal; processing the received data signal in the device that isexternal to the patient; and storing the processed data signal in amemory.
 11. The method of claim 10 wherein the implanted device isleadless and the generated wireless signal and received wireless datasignal are radiofrequency signals.
 12. The method of claim 10 whereinprocessing the received data signal comprises extracting features fromthe neural signal and classifying the extracted features to estimate thepatient's brain state that is indicative of the patient's propensity fora neurological event.
 13. The method of claim 12 further comprisinggenerating an output on a user interface of the device that is externalto the patient that is indicative of the patient's brain state.
 14. Themethod of claim 11 wherein the wireless data signal from the leadlessimplanted device is encrypted, wherein processing the received datasignal comprises decrypting the data signal.
 15. The method of claim 10wherein the wireless data signal is further encoded with an extractedfeature that is indicative of the patient's brain state.
 16. The methodof claim 11 further comprising generating an output communication whenthe device external to the patient is not receiving the wireless datasignal from the leadless implanted device.
 17. A method of monitoringand recording EEG signals from a patient, the method comprising:minimally invasively implanting a leadless device between the patient'sscalp and skull; generating a radiofrequency signal in an externaldevice; receiving the radiofrequency signal with an antenna of theimplanted leadless device and using the radiofrequency signal to powerup and interrogate components of the implanted device; sampling an EEGsignal with electrodes on the implanted leadless device; transmitting areturn radiofrequency signal substantially continuously from theimplanted leadless device, wherein the return radiofrequency signal isencoded with the EEG signal; receiving the return radiofrequency signalencoded with the EEG signal in the external device; processing thereturn radiofrequency signal with the encoded EEG signal in the externaldevice; and storing the processed return radiofrequency signal in amemory of the external device.
 18. The method of claim 17 furthercomprising encrypting the sampled EEG signal prior to transmitting thereturn radiofrequency signal.
 19. The method of claim 17 furthercomprising generating an output communication when the external deviceis not receiving the return radiofrequency signal from the leadlessimplanted device.
 20. The method of claim 17 wherein processing thereturn radiofrequency signal comprises extracting features from the EEGsignal and classifying the extracted features to estimate the patient'sbrain state, wherein the brain state is indicative of the patient'spropensity for a neurological event.
 21. The method of claim 20 furthercomprising generating an output on a user interface of the externaldevice that is indicative of the patient's brain state.
 22. The methodof claim 1 further comprising powering the electronic components of theimplanted device by deriving and storing power from patient-based energysources.
 23. A method of recording neural signals from a patient, themethod comprising: powering electronic components of an implanted deviceby deriving and storing power from patient-based energy sources;sampling the neural signal of the patient with electrodes coupled to theelectronic components of the implanted device; and substantiallycontinuously transmitting a wireless signal that is encoded with datathat is indicative of the sampled neural signal from the implanteddevice to a portable external device.
 24. The method of claim 23 whereinthe implanted device is positioned between the patient's scalp and anouter surface of the skull.
 25. The method of claim 23 furthercomprising analyzing the data in the portable external device insubstantially real-time in order to estimate the patient's brain state.